Mobile phone for treating a patient with dementia

ABSTRACT

Devices, systems and methods are disclosed that allow a patient to self-treat neurodegenerative diseases, such as dementia, Alzheimer&#39;s disease, ischemic stroke, post-concussion syndrome, chronic traumatic encephalopathy and the like by electrical noninvasive stimulation of a vagus nerve. The system comprises a handheld stimulator that is applied to the surface of the patient&#39;s neck, wherein the stimulator comprises or is joined to a smartphone. A camera of the smartphone may be used to position and reposition the stimulator to a particular location on the patient&#39;s neck. The system may also comprise a base station that is used to meter the charging of a rechargeable battery within the stimulator. The base station and stimulator transmit data to one another regarding the status of a stimulation session.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation in Part of U.S. Nonprovisionalapplication Ser. No. 14/292,491 filed 30 May 2014, which claims thebenefit of U.S. Provisional Application Ser. No. 62/001,004 filed 20 May2014; and is a Continuation in Part of U.S. Nonprovisional applicationSer. No. 13/858,114 filed 8 Apr. 2013, which claims the benefit of U.S.Provisional Application Ser. No. 61/752,895 filed 15 Jan. 2013; each ofwhich is incorporated herein by reference in its entirety for allpurposes.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingmedical conditions such as epilepsy wherein the patient uses the devicesand methods as self-treatment, without the direct assistance of ahealthcare professional. The energy impulses (and/or fields) that areused to treat those conditions comprise electrical and/orelectromagnetic energy, delivered non-invasively to the patient,particularly to a vagus nerve of the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. One of the most successful applications of modernunderstanding of the electrophysiological relationship between muscleand nerves is the cardiac pacemaker. Although origins of the cardiacpacemaker extend back into the 1800's, it was not until 1950 that thefirst practical, albeit external and bulky, pacemaker was developed. Thefirst truly functional, wearable pacemaker appeared in 1957, and in1960, the first fully implantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference). Because the leads are implanted within thepatient, the pacemaker is an example of an implantable medical device.

Another such example is electrical stimulation of the brain withimplanted electrodes (deep brain stimulation), which has been approvedfor use in the treatment of various conditions, including pain andmovement disorders such as essential tremor and Parkinson's disease[Joel S. PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu.Rev. Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92(2001):505-513; patent U.S. Pat. No.6,871,099, entitled Fully implantable microstimulator for spinal cordstimulation as a therapy for chronic pain, to WHITEHURST, et al].

The form of electrical stimulation that is most relevant to the presentinvention is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al; U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29(2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3,2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993(2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nervestimulation therapy in depression and epilepsy: therapeutic parametersettings. Acta. Neurol. Scand. 115(2007):23-33].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the procedures that are disclosed here do not involvesurgery, i.e., they are not implantable medical devices. Instead, thepresent devices and methods stimulate nerves by transmitting energy tonerves and tissue non-invasively. A medical procedure is defined asbeing non-invasive when no break in the skin (or other surface of thebody, such as a wound bed) is created through use of the method, andwhen there is no contact with an internal body cavity beyond a bodyorifice (e.g., beyond the mouth or beyond the external auditory meatusof the ear). Such non-invasive procedures are distinguished frominvasive procedures (including minimally invasive procedures) in thatthe invasive procedures insert a substance or device into or through theskin (or other surface of the body, such as a wound bed) or into aninternal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2,2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body. An electric field is inducedat a distance, causing electric current to flow within electricallyconducting bodily tissue. The electrical circuits for magneticstimulators are generally complex and expensive and use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil to produce a magneticpulse. The principles of electrical nerve stimulation using a magneticstimulator, along with descriptions of medical applications of magneticstimulation, are reviewed in: Chris HOVEY and Reza Jalinous, The Guideto Magnetic Stimulation, The Magstim Company Ltd, Spring Gardens,Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006. In contrast,the magnetic stimulators that have been disclosed by the presentApplicant are relatively simpler devices that use considerably smallercurrents within the stimulator coils. Accordingly, they are intended tosatisfy the need for simple-to-use and less expensive non-invasivemagnetic stimulation devices.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In co-pending, commonly assigned patent applications, Applicantdisclosed noninvasive electrical vagus nerve stimulation devices, whichare adapted, and for certain applications improved, in the presentdisclosure [application Ser. No. 13/183,765 and PublicationUS2011/0276112, entitled Devices and methods for non-invasive capacitiveelectrical stimulation and their use for vagus nerve stimulation on theneck of a patient, to SIMON et al.; application Ser. No. 12/964,050 andPublication US2011/0125203, entitled Magnetic Stimulation Devices andMethods of Therapy, to SIMON et al.; and other co-pending commonlyassigned applications that are cited therein, which are hereinincorporated by reference]. The present disclosure elaborates on theelectrical stimulation device, rather than the magnetic stimulationdevice that has similar functionality, with the understanding thatunless it is otherwise indicated, the elaboration could apply to eitherthe electrical or the magnetic nerve stimulation device. Because theearlier devices have already been disclosed, the present disclosurefocuses on what is new with respect to the earlier disclosures.

In the present disclosure, the stimulator is ordinarily applied by thepatient himself or herself, without the benefit of having a trainedhealthcare provider nearby. The primary advantage of theself-stimulation therapy is that it can be administered more or lessimmediately when symptoms occur, rather than having to visit thehealthcare provider at a clinic or emergency room. In addition, thepatient may administer the therapy on a daily basis (e.g., one ormultiple times/day) to prophylactically treat the disorder. The need forsuch a visit would only compound the aggravation that the patient isalready experiencing. Another advantage of the self-stimulation therapyis the convenience of providing the therapy in the patient's home orworkplace, which eliminates scheduling difficulties, for example, whenthe nerve stimulation is being administered for prophylactic reasons atodd hours of the day. Furthermore, the cost of the treatment may bereduced by not requiring the involvement of a trained healthcareprovider.

For the present medical applications, an electrical stimulator device isordinarily applied to the patient's neck. In a preferred embodiment ofthe invention, the stimulator comprises two electrodes that lieside-by-side within separate stimulator assemblies, wherein theelectrodes are separated by electrically insulating material. Eachelectrode and the patient's skin are in connected electrically throughan electrically conducting medium that extends from the skin to theelectrode.

The position and angular orientation of the device are adjusted about alocation on the neck until the patient perceives stimulation whencurrent is passed through the stimulator electrodes. The applied currentis increased gradually, first to a level wherein the patient feelssensation from the stimulation. The power is then increased, but is setto a level that is less than one at which the patient first indicatesany discomfort. The stimulator signal waveform may have a frequency andother parameters that are selected to produce a therapeutic result inthe patient.

The electrical stimulation is then typically applied for 90 seconds to30 minutes (usually 90-180 seconds), which is often sufficient to atleast partially relieve headache pain within 5 minutes. The treatmentthen causes patients to experience a very rapid relief from headachepain, as well as a rapid opening of the nasal passages withinapproximately 20 minutes. Effects of the treatment may last for 4 to 5hours or longer.

Despite the advantages of having a patient administer the nervestimulation by him or herself, such self-stimulation presents certainrisks and difficulties relating to safety and efficacy. In somesituations, the vagus nerve stimulator should be applied to the left orto the right vagus nerve, but not vice versa. For example, if thestimulator is applied to the left vagus nerve at the neck, it would workas prescribed, but if it were to be accidentally applied to the rightvagus nerve, the device could potentially cause cardiac problems. On theother hand, in some situations the stimulation may actually be mostbeneficial if applied to the right vagus nerve, and it may be relativelyless effective if applied to the left vagus nerve. Therefore, if thepatient is using the vagus nerve stimulator by himself or herself, itwould be useful for the device be designed so that it can be used onlyon the prescribed side of the neck. The present invention disclosesmethods for preventing inadvertent stimulation on the side of the neckthat is not prescribed.

In the present invention, noninvasive vagus nerve electrical stimulationis used to treat neurodegenerative diseases. Neurodegenerative diseasesresult from the deterioration of neurons, causing brain dysfunction. Thediseases are loosely divided into two groups—conditions affecting memorythat are ordinarily related to dementia and conditions causing problemswith movements. The most widely known neurodegenerative diseases includeAlzheimer (or Alzheimer's) disease and its precursor mild cognitiveimpairment (MCI), Parkinson's disease (including Parkinson's diseasedementia), and multiple sclerosis.

Less well-known neurodegenerative diseases include adrenoleukodystrophy,AIDS dementia complex, Alexander disease, Alper's disease, amyotrophiclateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovinespongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy,cerebellar ataxia, Cockayne syndrome, corticobasal degeneration,Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatalfamilial insomnia, Fazio-Londe disease, Friedreich's ataxia,frontotemporal dementia or lobar degeneration, hereditary spasticparaplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewybody dementia, Lyme disease, Machado-Joseph disease, motor neurondisease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pickdisease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateralsclerosis including its juvenile form, progressive bulbar palsy,progressive supranuclear palsy, Refsum's disease including its infantileform, Sandhoff disease, Schilder's disease, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacutecombined degeneration of the spinal cord, survival motor neuron spinalmuscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxicencephalopathy, transmissible spongiform encephalopathy, Vasculardementia, and X-linked spinal muscular atrophy, as well as idiopathic orcryptogenic diseases as follows: synucleinopathy, progranulinopathy,tauopathy, amyloid disease, prion disease, protein aggregation disease,and movement disorder. A more comprehensive listing may be found at theweb site (www) of the National Institute of Neurological Disorders andStroke (ninds) of the National Institutes of Health (nih) of the UnitedStates government (gov). It is understood that such diseases often go bymore than one name and that a disease classification may oversimplifypathologies that occur in combination or that are not archetypical.

Despite the fact that at least some aspect of the pathology of each ofthe neurodegenerative diseases mentioned above is different from theother diseases, their pathologies ordinarily share other features, sothat they may be considered as a group. Furthermore, aspects of theirpathologies that they have in common often make it possible to treatthem with similar therapeutic methods. Thus, many publications describefeatures that neurodegenerative diseases have in common [Dale E.BREDESEN, Rammohan V. Rao and Patrick Mehlen. Cell death in the nervoussystem. Nature 443(2006): 796-802; Christian HAASS. Initiation andpropagation of neurodegeneration. Nature Medicine 16(11,2010):1201-1204; Eng H L O. Degeneration and repair in central nervous systemdisease. Nature Medicine 16(11,2010):1205-1209; Daniel M. SKOVRONSKY,Virginia M.-Y. Lee, and John Q. TROJANOWSKI. Neurodegenerative Diseases:New Concepts of Pathogenesis and Their Therapeutic Implications. Annu.Rev. Pathol. Mech. Dis. 1(2006): 151-70; Michael T. LIN and M. FlintBeal. Mitochondrial dysfunction and oxidative stress inneurodegenerative diseases. Nature 443(2006): 787-795; Jorge J. PALOP,Jeannie Chin and Lennart Mucke. A network dysfunction perspective onneurodegenerative diseases. Nature 443(2006): 768-773; David C.RUBINSZTEIN. The roles of intracellular protein-degradation pathways inneurodegeneration. Nature 443(2006): 780-786].

The present invention is concerned primarily with the treatmentneurodegenerative diseases, such as dementia, Alzheimer's disease,ischemic stroke, post-traumatic concussion, chronic traumaticencephalopathy and the like.

Dementia is a clinical diagnosis that is based on evidence of cognitivedysfunction in both the patient's history and in successive mentalstatus examinations. The diagnosis is made when there is impairment intwo or more of the following: learning and retaining newly acquiredinformation (episodic declarative memory); handling complex tasks andreasoning abilities (executive cognitive functions); visuospatialability and geographic orientation; and language functions. Thediagnosis may be made after excluding potentially treatable disordersthat may otherwise contribute to cognitive impairment, such asdepression, vitamin deficiencies, hypothyroidism, tumor, subduralhematomas, central nervous system infection, a cognitive disorderrelated to human immunodeficiency virus infection, adverse effects ofprescribed medications, and substance abuse [McKHANN G, Drachman D,Folstein M, Katzman R, Price D, Stadlan E M. Clinical diagnosis ofAlzheimer's disease: report of the NINCDS-ADRDA Work Group under theauspices of Department of Health and Human Services Task Force onAlzheimer's Disease. Neurology 34(7,1984):939-44; David S. KNOPMAN.Alzheimer's Disease and other dementias. Chapter 409 (pp. 2274-2283) In:Goldman's Cecil Medicine, 24th Edn. (Lee Goldman and Andrew I. Schafer,Eds.). Philadelphia: Elsevier-Saunders, 2012; THOMPSON S B. AlzheimersDisease: Comprehensive Review of Aetiology, Diagnosis, AssessmentRecommendations and Treatment. Webmed Central AGING 2011; 2(3):WMC001681, pp. 1-42].

Dementia prevalence increases with age, from 5% of those aged 71-79years to 37% of those aged 90 and older. However, despite theirprevalence in old age, dementias such as Alzheimer's disease are not anintegral part of the aging process [NELSON P T, Head E, Schmitt F A,Davis P R, Neltner J H, Jicha G A, Abner E L, Smith C D, Van Eldik L J,Kryscio R J, Scheff S W. Alzheimer's disease is not “brain aging”:neuropathological, genetic, and epidemiological human studies. ActaNeuropathol 121(5,2011):571-87]. Genetics plays a role in early-onset AD(less than 1% of cases). The most powerful genetic risk factor for themore common forms of AD is the APOE e4 gene, one or more copies of whichare carried by 60% of AD patients in some populations. Otherwise, therisk of AD may be increased by a low level of education, severe headinjury, cerebrovascular disease, diabetes and obesity.

The principal diseases that cause dementia are three neurodegenerativediseases (Alzheimer's disease, Lewy body disease, and frontotemporallobar degeneration) and cerebrovascular disease. In the United States,Alzheimer's disease accounts for approximately 70% of cases of dementia,and vascular dementia accounts for 17% of cases. Lewy body dementia andfrontotemporal lobar dementia account for the remaining 13% of cases,along with less common causes (e.g., alcoholic/toxic dementia, traumaticbrain injury, normal-pressure hydrocephalus, Parkinson's dementia,Creutzfeldt-Jakob disease, and undetermined etiology). In absolutenumbers, it is estimated that about 5.4 million Americans are currentlyliving with Alzheimer's disease, and Lewy Body dementia affects about1.3 million Americans.

Patients with each type of dementia exhibit certain typical symptoms. InAlzheimer's disease, anterograde amnesia is a dominant symptom—loss ofthe ability to create new memories of events occurring after the onsetof the disease. Dementia with Lewy bodies is characterized byparkinsonism, visual hallucinations, and a rapid-eye-movement sleepdisorder. Frontotemporal lobar degeneration is characterized byprominent behavioral and personality changes or by prominent languagedifficulties early in the course of the disease. Cerebrovasculardementia, which may be a sequela of atherosclerosis, is due to one ormore cerebral infarctions (ischemic strokes) in brain locations that areresponsible for the cognitive deficits. The simultaneous presence ofAlzheimer's disease with vascular dementia is common, and it may bedifficult to distinguish these two dementia on the basis of symptomsalone.

Hour-to-hour and day-to-day changes in cognition may also be exhibitedby individuals with dementia. Thus, caregivers of patients with dementiaoften notice that the patient may be confused and incoherent at onetime, and only a few hours later, or the next day, the patient is alertand coherent. The time-course and situational antecedent of thoseso-called cognitive fluctuations may also be helpful in distinguishingone form of dementia from the others, using clinical scales have beendeveloped to analyze such fluctuations (Clinician Assessment ofFluctuation, One Day Fluctuation Assessment Scale, Mayo FluctuationQuestionnaire). Dementia with Lewy bodies is associated with transientand spontaneous episodes of confusion and an inability to engage inmeaningful cognitive activity, followed by reversion to a near normallevel of function, often within hours. In contrast, cognitivefluctuations in Alzheimer's disease are often elicited by situations inwhich an underlying cognitive impairment manifests itself, typically asrepetitiveness in conversation, forgetfulness in relation to a recenttask or event, or other behavioral consequences of poor memory. Inaddition to this situational triggering aspect of a cognitivefluctuation in patients with Alzheimer's disease, the confusion is oftena more enduring state shift (good days/bad days), rather than anhour-to-hour shift.

The mechanism of cognitive fluctuation is unknown, either for thehour-to-hour type that is common in dementia with Lewy bodies, or theday-to-day type that is not uncommon among Alzheimer patients. However,the mechanism is clearly different than the ones involved in circadianphenomena, such as “sundowning,” because the cognitive fluctuation neednot occur around a particular time of day. Whatever the mechanism ofcognitive fluctuations, it would be very beneficial to be able toprevent or reverse them, if only as a prophylactic or symptomatictreatment, so as to spare the patient and caregiver of the stressassociated with fluctuating cognitive impairment as it relates toimpairment of activities of daily living [Jorge J. PALOP, Jeannie Chinand Lennart Mucke. A network dysfunction perspective onneurodegenerative diseases. Nature 443(7113,2006):768-73; WALKER M P,Ayre G A, Cummings J L, Wesnes K, McKeith I G, O'Brien J T, Ballard C G.The Clinician Assessment of Fluctuation and the One Day FluctuationAssessment Scale. Two methods to assess fluctuating confusion indementia. Br J Psychiatry 177(2000):252-6; BRADSHAW J, Saling M, HopwoodM, Anderson V, Brodtmann A. Fluctuating cognition in dementia with Lewybodies and Alzheimer's disease is qualitatively distinct. J NeurolNeurosurg Psychiatry 75(3,2004):382-7; BALLARD C, Walker M, O'Brien J,Rowan E, McKeith I. The characterisation and impact of ‘fluctuating’cognition in dementia with Lewy bodies and Alzheimer's disease. Int JGeriatr Psychiatry 16(5,2001):494-8; CUMMINGS J L. Fluctuations incognitive function in dementia with Lewy bodies. Lancet Neurol3(5,2004):266; David R. LEE, John-Paul Taylor, Alan J. Thomas.Assessment of cognitive fluctuation in dementia: a systematic review ofthe literature. International Journal of Geriatric Psychiatry 27(10,2012): 989-998; BACHMAN D, Rabins P. “Sundowning” and other temporallyassociated agitation states in dementia patients. Annu Rev Med57(2006):499-511].

As described above, dementia is a clinical diagnosis that is based onevidence of cognitive dysfunction in both the patient's history and insuccessive mental status examinations. With the ability to better stagethe progression of dementia, treatment might be justified at stagesprior to actual onset of the dementia. In particular, the presentinvention might best be used early in the course of the diseaseprogression, such that treatment could be directed to slowing, stopping,or even reversing the pathophysiological processes underlying thedementia. Thus, the present invention contemplates treatments even whenthe patient exhibits prodromal symptoms or when the patient has beendiagnosed with mild cognitive impairment (MCI) [DeCARLI C. Mildcognitive impairment: prevalence, prognosis, aetiology, and treatment.Lancet Neurol 2(1,2003):15-21; MAYEUX R. Clinical practice. EarlyAlzheimer's disease. N Engl J Med 362(23,2010):2194-2201; WILSON R S,Leurgans S E, Boyle P A, Bennett D A. Cognitive decline in prodromalAlzheimer disease and mild cognitive impairment. Arch Neurol68(3,2011):351-356].

Early staging of the patient's disease progression makes use ofbiomarkers, which are cognitive, physiological, biochemical, andanatomical variables that can be measured in a patient that indicate theprogression of a dementia such as AD. The most commonly measuredbiomarkers for AD include decreased Aβ42 in the cerebrospinal fluid(CSF), increased CSF tau, decreased fluorodeoxyglucose uptake on PET(FDG-PET), PET amyloid imaging, and structural MRI measures of cerebralatrophy. Use of biomarkers to stage AD has developed to the point thatbiomarkers can be used with revised criteria for diagnosing the disease[MASDEU J C, Kreisl W C, Berman K F. The neurobiology of Alzheimerdisease defined by neuroimaging. Curr Opin Neurol 25(4,2012):410-420;DUBOIS B, Feldman H H, Jacova C, Dekosky S T, Barberger-Gateau P,Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K,O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer'sdisease: revising the NINCDS-ADRDA criteria. Lancet Neurol6(8,2007):734-46; GAUTHIER S, Dubois B, Feldman H, Scheltens P. Revisedresearch diagnostic criteria for Alzheimer's disease. Lancet Neurol 7(8,2008): 668-670].

In the remainder of this background section, current methods of treatingAD are described. As summarized here, they include methods to treatcognitive symptoms of AD patients, as well as methods that are intendedto treat the underlying pathophysiological progression of AD. Becausethe methods described in the publications cited below have not beendemonstrated to exhibit more than very modest success in treating onlysymptoms of AD, and no method is known to stop the progression of AD,additional methods are clearly needed, which motivates the inventionthat is disclosed here. Because the disclosure involves vagus nervestimulation, the effect of stimulation on the patient's locus ceruleus,and consequences of that effect, the literature relevant to thosesubjects is emphasized in what follows.

Before the currently favored amyloid cascade hypothesis of AD (andsubsequent variants of that hypothesis), the focus of AD research wasthe search for a clearly defined neurochemical abnormality in ADpatients, which would provide the basis for the development of rationaltherapeutic interventions that are analogous to levodopa treatment ofParkinson's disease. This led to the cholinergic hypothesis ofAlzheimer's disease, which proposed that degeneration of cholinergicneurons in the basal forebrain and the associated loss of cholinergicneurotransmission in the cerebral cortex and other areas contributedsignificantly to the deterioration in cognitive function seen inpatients with Alzheimer's disease. The symptomatic drug treatments thatarose from that research are currently the mainstay of AD treatment,even though their effectiveness is very modest, and no drug delays theprogression of the disease. Approved drugs for the symptomatic treatmentof AD modulate neurotransmitters—either acetylcholine or glutamate:cholinesterase inhibitors (tacrine, rivastigmine, galantamine anddonepezil) and partial N-methyl-D-aspartate antagonists (memantine)[FRANCIS P T, Ramirez M J, Lai M K. Neurochemical basis for symptomatictreatment of Alzheimer's disease. Neuropharmacology59(4-5,2010):221-229; FRANCIS P T, Palmer A M, Snape M, Wilcock G K. Thecholinergic hypothesis of Alzheimer's disease: a review of progress. JNeurol Neurosurg Psychiatry 66(2,1999):137-47; MESULAM M. Thecholinergic lesion of Alzheimer's disease: pivotal factor or side show?Learn Mem 11(1,2004):43-49].

The symptomatic treatment of AD by modulating neurotransmitters otherthan acetylcholine or glutamate has also been considered. One suchneurotransmitter is norepinephrine (noradrenaline), which in the brainis principally synthesized in the locus ceruleus. A rationale fortherapeutic modulation of norepinephrine levels has been that in AD,there is loss of noradrenergic neurons in the locus ceruleus, and thetreatment would compensate for that loss [HAGLUND M, Sjobeck M, EnglundE. Locus ceruleus degeneration is ubiquitous in Alzheimer's disease:possible implications for diagnosis and treatment. Neuropathology26(6,2006):528-32; SAMUELS E R, Szabadi E. Functional neuroanatomy ofthe noradrenergic locus coeruleus: its roles in the regulation ofarousal and autonomic function part II: physiological andpharmacological manipulations and pathological alterations of locuscoeruleus activity in humans. Curr Neuropharmacol 6(3,2008):254-85;Patricia SZOT. Common factors among Alzheimer's disease, Parkinson'sdisease, and epilepsy: Possible role of the noradrenergic nervoussystem. Epilepsia 53(Suppl. 1,2012):61-66].

Accordingly, several investigators proposed to increase brainnorepinephrine as a therapy for AD patients [E M VAZEY, V K Hinson, A CGranholm, M A Eckert, G A Jones. Norepinephrine in Neurodegeneration: ACoerulean Target. J Alzheimers Dis Parkinsonism 2(2,2012):1000e114, pp.1-3]. Administration of norepinephrine itself is not feasible as amethod for increasing its levels in the central nervous system becausenorepinephrine, as with other catecholamines, cannot cross theblood-brain barrier. Many other drugs such as amphetamines andmethylphenidate can increase norepinephrine brain levels, but theyaffect other neurotransmitter systems as well and have significant sideeffects. Consequently, less direct methods have been used or suggestedas ways to increase norepinephrine levels in the central nervous system,or to activate adrenergic signaling. They include the use of specialdrugs that mimic norepinephrine, that serve as precursors ofnorepinephrine, that block the reuptake of norepinephrine, and thatserve as adrenoceptor antagonists that enhances norepinephrine release[MISSONNIER P, Ragot R, Derouesné C, Guez D, Renault B. Automaticattentional shifts induced by a noradrenergic drug in Alzheimer'sdisease: evidence from evoked potentials. Int J Psychophysiol33(3,1999): 243-51; FRIEDMAN J I, Adler D N, Davis K L. The role ofnorepinephrine in the pathophysiology of cognitive disorders: potentialapplications to the treatment of cognitive dysfunction in schizophreniaand Alzheimer's disease. Biol Psychiatry. 46(9,1999):1243-52; KALININ S,Polak P E, Lin S X, Sakharkar A J, Pandey S C, Feinstein D L. Thenoradrenaline precursor L-DOPS reduces pathology in a mouse model ofAlzheimer's disease. Neurobiol Aging 33(8,2012):1651-1663; MOHS, R. C.,Shiovitz, T. M., Tariot, P. N., Porsteinsson, A. P., Baker, K. D.,Feldman, P. D., 2009. Atomoxetine augmentation of cholinesteraseinhibitor therapy in patients with Alzheimer disease: 6-month,randomized, double-blind, placebo-controlled, parallel-trial study. Am.J. Geriatr. Psychiatry 17, 752-759; SCULLION G A, Kendall D A, Marsden CA, Sunter D, Pardon M C. Chronic treatment with the a2-adrenoceptorantagonist fluparoxan prevents age-related deficits in spatial workingmemory in APP×PS1 transgenic mice without altering R-amyloid plaque loador astrocytosis. Neuropharmacology 60(2-3,2011):223-34]. Other agentsthat are thought to alter norepinephrine levels, via locus ceruleusactivity, include chronic stress, chronic opiate treatment, andanti-depressant treatment [NESTLER E J, Alreja M, Aghajanian G K.Molecular control of locus coeruleus neurotransmission. Biol Psychiatry46(9,1999):1131-1139; SAMUELS, E. R., and Szabadi, E. Functionalneuroanatomy of the noradrenergic locus coeruleus: its roles in theregulation of arousal and autonomic function part II: physiological andpharmacological manipulations and pathological alterations of locuscoeruleus activity in humans. Curr. Neuropharmacol. 6(2008), 254-285].

However, for several reasons, it is not settled that apharmacologically-induced increase of norepinephrine, or increasedsignaling through the adrenergic receptors in the central nervoussystem, will substantially benefit AD patients. First, in patients withAD, clonidine (a centrally acting alpha2 adrenergic agonist) wasreported to have no effect on cognitive functions, and may even impairsustained attention and memory. Another putative alpha2-adrenoceptoragonist, guanfacine, has consistently been shown to be without effect oncognitive functions. Thus, administration of clonidine or guanfacinedoes not appear to provide any consistent improvement in cognitivefunctions, either in normal subjects or in patients with AD or othercognitive impairments. On the other hand, the alpha2-adrenoceptorantagonist, idazoxan, improved planning, sustained attention, verbalfluency, and episodic memory but impaired spatial working memory inpatients with dementia of the frontal type [MARIEN M R, Colpaert F C,Rosenquist A C. Noradrenergic mechanisms in neurodegenerative diseases:a theory. Brain Res Brain Res Rev 45(1,2004):38-78].

Second, norepinephrine significantly worsens agitation and anxiety in ADpatients, such that any potential benefits of increased norepinephrinelevels may be offset by behavioral side effects, as well ascardiovascular side effects [HERRMANN N, Lanctôt K L, Khan L R. The roleof norepinephrine in the behavioral and psychological symptoms ofdementia. J Neuropsychiatry Clin Neurosci 16(3,2004):261-76; PESKIND, E.R., Tsuang, D. W., Bonner, L. T., Pascualy, M., Riekse, R. G., Snowden,M. B., Thomas, R., Raskind, M. A. Propranolol for disruptive behaviorsin nursing home residents with probable or possible Alzheimer disease: aplacebo-controlled study. Alzheimer Dis. Assoc. Disord. 19(2005):23-28].

Third, loss of locus ceruleus cells in AD may lead to compensatoryproduction of norepinephrine in other cells, such that there mayactually be an increase in norepinephrine levels in some AD patients[Fitzgerald P J. Is elevated norepinephrine an etiological factor insome cases of Alzheimer's disease? Curr Alzheimer Res 7(6,2010):506-16;ELROD R, Peskind E R, DiGiacomo L, Brodkin K I, Veith R C, Raskind M A.Effects of Alzheimer's disease severity on cerebrospinal fluidnorepinephrine concentration. Am J Psychiatry 154(1,1997):25-30].

Even if there is a decrease in overall brain norepinephrine levels inAD, this decrease does not necessarily occur uniformly among brainregions that are modulated by the locus ceruleus, and patterns ofcompensatory receptor alterations may also be complicated, withselective decreases and increases of noradrenergic receptors subtypes indifferent regions of the brain [HOOGENDIJK W J, Feenstra M G, BotterblomM H, Gilhuis J, Sommer I E, Kamphorst W, Eikelenboom P, Swaab D F.Increased activity of surviving locus ceruleus neurons in Alzheimer'sdisease. Ann Neurol 45(1,1999):82-91; SZOT P, White S S, Greenup J L,Leverenz J B, Peskind E R, Raskind M A. Compensatory changes in thenoradrenergic nervous system in the locus coeruleus and hippocampus ofpostmortem subjects with Alzheimer's disease and dementia with LewyBodies. J Neurosci 26(2006):467-478; SZOT P, White S S, Greenup J L,Leverenz J B, Peskind E R, Raskind M A. Changes in adrenoreceptors inthe prefrontal cortex of subjects with dementia: evidence ofcompensatory changes. Neuroscience 146(2007):471-480].

Therefore, what is needed is not a pharmacological method that increasesnorepinephrine levels indiscriminately throughout the central nervoussystem of AD patients, but rather a method that can selectively increase(or decrease) the norepinephrine levels only where it is needed. This istrue whether the increase is intended to improve cognition or whetherthe increase in norepinephrine levels is intended to prevent, delay orantagonize pathological biochemical changes that occur in the brains ofAD patients [COUNTS S E, Mufson E J. Noradrenaline activation ofneurotrophic pathways protects against neuronal amyloid toxicity. JNeurochem 113(3,2010):649-60; WENK G L, McGann K, Hauss-Wegrzyniak B,Rosi S. The toxicity of tumor necrosis factor-alpha upon cholinergicneurons within the nucleus basalis and the role of norepinephrine in theregulation of inflammation: implications for Alzheimer's disease.Neuroscience 121(3,2003):719-29; KALININ S, Gavrilyuk V, Polak P E,Vasser R, Zhao J, Heneka M T, Feinstein D L. Noradrenaline deficiency inbrain increases beta-amyloid plaque burden in an animal model ofAlzheimer's disease. Neurobiol Aging 28(8,2007):1206-1214; HENEKA M T,Ramanathan M, Jacobs A H, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T,Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss W D, Klockgether T,Staufenbiel M. Locus ceruleus degeneration promotes Alzheimerpathogenesis in amyloid precursor protein 23 transgenic mice. JNeurosci. 26(5,2006):1343-54; HENEKA M T, Nadrigny F, Regen T,Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-KurutzD, Walter J, Kirchhoff F, Hanisch U K, Kummer M P. Locus ceruleuscontrols Alzheimer's disease pathology by modulating microglialfunctions through norepinephrine. Proc Natl Acad Sci USA.107(13,2010):6058-6063; JARDANHAZI-KURUTZ D, Kummer M P, Terwel D, VogelK, Thiele A, Heneka M T. Distinct adrenergic system changes andneuroinflammation in response to induced locus ceruleus degeneration inAPP/PS1 transgenic mice. Neuroscience 176(2011):396-407; YANG J H, Lee EO, Kim S E, Suh Y H, Chong Y H. Norepinephrine differentially modulatesthe innate inflammatory response provoked by amyloid-R peptide viaaction at R-adrenoceptors and activation of cAMP/PKA pathway in humanTHP-1 macrophages. Exp Neurol 236(2,2012):199-206; KONG Y, Ruan L, QianL, Liu X, Le Y. Norepinephrine promotes microglia to uptake and degradeamyloid beta peptide through upregulation of mouse formyl peptidereceptor 2 and induction of insulin-degrading enzyme. J Neurosci30(35,2012):11848-11857; KALININ S, Polak P E, Lin S X, Sakharkar A J,Pandey S C, Feinstein D L. The noradrenaline precursor L-DOPS reducespathology in a mouse model of Alzheimer's disease. Neurobiol Aging33(8,2012):1651-1663; HAMMERSCHMIDT T, Kummer M P, Terwel D, Martinez A,Gorji A, Pape H C, Rommelfanger K S, Schroeder J P, Stoll M, Schultze J,Weinshenker D, Heneka M T. Selective Loss of Noradrenaline ExacerbatesEarly Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice. BiolPsychiatry. 2012 Aug. 9. Epub ahead of print, pp. 1-10; O'DONNELL J,Zeppenfeld D, McConnell E, Pena S, Nedergaard M. Norepinephrine: ANeuromodulator That Boosts the Function of Multiple Cell Types toOptimize CNS Performance. Neurochem Res. 2012 Jun. 21. (Epub ahead ofprint}, pp. 1-17].

Psychotropic medications are also used in conjunction with theneurotransmitter modulators to treat secondary symptoms of AD such asdepression, agitation, and sleep disorders [Julius POPP and Sonke Arlt.Pharmacological treatment of dementia and mild cognitive impairment dueto Alzheimer's disease. Current Opinion in Psychiatry 24(2011):556-561;Fadi MASSOUD and Gabriel C Leger. Pharmacological treatment of Alzheimerdisease. Can J Psychiatry. 56(10,2011):579-588; Carl H. SADOWSKY andJames E. Galvin. Guidelines for the management of cognitive andbehavioral problems in dementia. J Am Board Fam Med 25(2012):350-366].

Therapies directed to modifying AD progression itself are consideredinvestigational. These include treatment of the intense inflammationthat occurs in the brains of patients with AD, estrogen therapy, use offree-radical scavengers, therapies designed to decrease toxic amyloidfragments in the brain (vaccination, anti-amyloid antibodies, selectiveamyloid-lowering agents, chelating agents to prevent amyloidpolymerization, brain shunting to improve removal of amyloid, andbeta-secretase inhibitors to prevent generation of the A-beta amyloidfragment), and agents that may prevent or reverse excess tauphosphorylation and thereby diminish formation of neurofibrillarytangles. Some agents, such as retinoids, may target multiple aspects ofAD pathogenesis [TAYEB H O, Yang H D, Price B H, Tarazi F I.Pharmacotherapies for Alzheimer's disease: beyond cholinesteraseinhibitors. Pharmacol Ther 134(1,2012):8-25; LEMER A J,Gustaw-Rothenberg K, Smyth S, Casadesus G. Retinoids for treatment ofAlzheimer's disease. Biofactors 38(2,2012):84-89; KURZ A, Perneczky R.Novel insights for the treatment of Alzheimer's disease. ProgNeuropsychopharmacol Biol Psychiatry 35(2,2011):373-379; MINATI L,Edginton T, Bruzzone M G, Giaccone G. Current concepts in Alzheimer'sdisease: a multidisciplinary review. Am J Alzheimers Dis Other Demen24(2,2009):95-121].

However, it is increasingly recognized that a single target orpathogenic pathway for the treatment of AD is unlikely to be identified.The best strategy is thought to be a multi-target therapy that includesmultiple types of treatments [MANGIALASCHE F, Solomon A, Winblad B,Mecocci P, Kivipelto M. Alzheimer disease: clinical trials and drugdevelopment. Lancet Neurol 9(7,2010):702-716]. Targets in thatmulti-target approach will include inflammatory pathways, and severaltherapeutic agents have been proposed to target them—nonsteroidalanti-inflammatory drugs, statins, RAGE antagonists and antioxidants[STUCHBURY G, Munch G. Alzheimer associated inflammation, potential drugtargets and future therapies. J Neural Transm. 2005 March; 112(3):429-53Joseph BUTCHART and Clive Holmes. Systemic and Central Immunity inAlzheimer's Disease:Therapeutic Implications. CNS Neuroscience &Therapeutics 18(2012): 64-76]. Another such agent, Etanercept, targetsTNF-alpha, but its use has the disadvantage that because it does notpass the blood-brain barrier (BBB), its administration is via a painfulspinal route or via an experimental method to get through the BBB [U.S.Pat. No. 7,640,062, entitled Methods and systems for management ofalzheimer's disease, to SHALEV]. One TNF-inhibitor that does not havethis disadvantage is thalidomide [Tweedie D, Sambamurti K, Greig N H:TNF-alpha Inhibition as a Treatment Strategy for NeurodegenerativeDisorders: New Drug Candidates and Targets. Curr Alzheimer Res 2007,4(4):375-8]. However, thalidomide is well known by the public to causebirth defects, and in a small trial, its use did not appear to improvecognition in AD patients [Peggy PECK. IADRD: Pilot Study of Thalidomidefor Alzheimer's Disease Fails to Detect Cognitive Benefit but FindsEffect on TNF-alpha. Doctor's Guide Global Edition, Jul. 26, 2002].

Various devices have been proposed to restore or enhance cognition,including cognition of AD patients [Mijail Demian SERRUYA and Michael J.Kahana. Techniques and devices to restore cognition. Behav Brain Res192(2,2008): 149-165]. Deep brain electrical stimulation has beengenerally unsuccessful or counterproductive in attempting to enhance thememory of AD patients. However, improved verbal recall has been observedin one case study in which deep-brain stimulation of the hypothalamusand fornix was used to treat morbid obesity [HAMANI C, McAndrews M P,Cohn M, Oh M, Zumsteg D, Shapiro C M, Wennberg R A, Lozano A M. Memoryenhancement induced by hypothalamic/fornix deep brain stimulation. AnnNeurol 63(2008):119-23; Adrian W. LAXTON and Andres M. Lozano. Deepbrain stimulation for the treatment of Alzheimer disease and dementias.World Neurosurg. (2012), pp. 1-8]. Entorhinal, but not hippocampal, deepbrain stimulation has also been found to improve memory used in spatialnavigation. Authors of that investigation suggest that in usingneuroprosthetic devices for purposes of cognitive enhancement,stimulation may not need to be applied continuously, but instead onlywhen patients are attempting to learn important information. They alsosuggest that resetting of the phase of the theta rhythm in the EEG (3-8Hz) improves memory performance, as has been observed in animalexperiments [Nanthia SUTHANA, Zulfi Haneef, John Stern, Roy Mukamel,Eric Behnke, Barbara Knowlton and Itzhak Fried. Memory enhancement anddeep-brain stimulation of the entorhinal area. N Engl J Med366(2012):502-10; LEMON N, Aydin-Abidin S, Funke K, Manahan-Vaughan D.Locus coeruleus activation facilitates memory encoding and induceshippocampal LTD that depends on beta-adrenergic receptor activation.Cereb Cortex 19(12,2009):2827-37].

Magnetic stimulation of AD patients has also been performed, but its usehas been intended only to affect cognitive skills and only usingtranscranial magnetic stimulation [Mamede de CARVALHO, Alexandre deMendonga, Pedro C. Miranda, Carlos Garcia and Maria Lourdes Sales Luis.Magnetic stimulation in Alzheimer's disease. Journal of Neurology 244(1997, 5): 304-307; COTELLI M, Manenti R, Cappa S F, Zanetti O, MiniussiC. Transcranial magnetic stimulation improves naming in Alzheimerdisease patients at different stages of cognitive decline. Eur J Neurol.15(12, 2008):1286-92; GUSE B, Falkai P, Wobrock T. Cognitive effects ofhigh-frequency repetitive transcranial magnetic stimulation: asystematic review. J Neural Transm. 117(1,2010):105-22; RaffaeleNARDONE, Jurgen Bergmann, Monica Christova, Francesca Caleri, FredianoTezzon, Gunther Ladurner, Eugen Trinka and Stefan Golaszewski. Effect oftranscranial brain stimulation for the treatment of Alzheimer disease: Areview. International Journal of Alzheimer's Disease 2012, Article ID687909: pp. 1-5; Raffaele NARDONE, Stefan Golaszewski, Gunther Ladurner,Frediano Tezzon, and Eugen Trinka. A Review of Transcranial MagneticStimulation in the in vivo Functional Evaluation of Central CholinergicCircuits in Dementia. Dement Geriatr Cogn Disord 32(2011):18-25].

A method of using vagal nerve stimulation to treat AD symptoms wasdisclosed in U.S. Pat. No. 5,269,303, entitled Treatment of dementia bynerve stimulation, to WERNICKE et al. It is directed to “a symptom ofdementia” which was described as being either paroxysmal activityexhibited in the patient's EEG or the level of alertness of the patient,but not to cognition per se.

In 2002, it was reported that electrical stimulation of the vagus nervehas a beneficial effect on cognition in patients with AD [SJOGREN M J,Hellström P T, Jonsson M A, Runnerstam M, Silander H C, Ben-Menachem E.Cognition-enhancing effect of vagus nerve stimulation in patients withAlzheimer's disease: a pilot study. J Clin Psychiatry63(11,2002):972-80]. The rationale for that trial was that vagus nervestimulation had previously been found to enhance the cognitive abilitiesof patients that were undergoing vagus nerve stimulation for otherconditions such as epilepsy and depression, as well as enhancedcognitive abilities observed in animal studies. Results concerning theAD patients' improved cognitive abilities over a longer period of time,along with improvement in tau protein of cerebrospinal fluid, weresubsequently reported [MERRILL C A, Jonsson M A, Minthon L, Ejnell H,C-son Silander H, Blennow K, Karlsson M, Nordlund A, Rolstad S,Warkentin S, Ben-Menachem E, Sjögren M J. Vagus nerve stimulation inpatients with Alzheimer's disease: Additional follow-up results of apilot study through 1 year. J Clin Psychiatry. 2006 August;67(8):1171-8]. Those results were immediately greeted with skepticism,particularly the purported changes in tau protein, because there was nocontrol group and the number of patients was small [Theresa DEFINO.Symptoms stable in AD patients who underwent vagus nerve stimulation.Neurology Today 6(21,2006):14-15].

Stimulation of the vagus nerve to treat at least the symptomaticcognitive aspects of dementia might be more effective than stimulationof nerves found in locations such as the spine, forehead, and earlobes[CAMERON M H, Lonergan E, Lee H. Transcutaneous Electrical NerveStimulation (TENS) for dementia. Cochrane Database of Systematic Reviews2003, Issue 3. Art. No.: CD004032. (2009 update); Erik J. A. SCHERDER,Marijn W. Luijpen, and Koene R. A. van Dijk. Activation of the dorsalraphe nucleus and locus coeruleus by transcutaneous electrical nervestimulation in Alzheimer's disease: a reconsideration ofstimulation-parameters derived from animal studies. Chinese Journal ofPhysiology 46(4,2003): 143-150]. However, BOON and colleagues disputethe claim that vagus nerve stimulation with prevailing stimulationparameters can enhance even the cognitive abilities of human patients,although they do conclude that such stimulation can improve cognition inanimal models [Paul BOON, Ine Moors, Veerle De Herdt, Kristl Vonck.Vagus nerve stimulation and cognition. Seizure15(2006), 259-263]. Infact, in humans, vagus nerve stimulation impairs cognitive flexibilityand creative thinking [GHACIBEH G A, Shenker J I, Shenal B, Uthman B M,Heilman K M. Effect of vagus nerve stimulation on creativity andcognitive flexibility. Epilepsy Behav 8(4,2006):720-725]. Furthermore,it has no effect on learning, but it might enhance memory consolidation,which leads to improved retention [GHACIBEH G A, Shenker J I, Shenal B,Uthman B M, Heilman K M. The influence of vagus nerve stimulation onmemory. Cogn Behav Neurol 19(3,2006):119-22; CLARK K B, Naritoku D K,Smith D C, Browning R A, Jensen R A. Enhanced recognition memoryfollowing vagus nerve stimulation in human subjects. Nature Neurosci2(1999):94-98]. Among different types of memories, vagus nervestimulation is reported to improve only verbal recognition memory[McGLONE J, Valdivia I, Penner M, Williams J, Sadler R M, Clarke D B.Quality of life and memory after vagus nerve stimulator implantation forepilepsy. Can J Neurol Sci 35(3,2008):287-96]. However, most suchinvestigations have been performed on patients with electrodes implantedto control epilepsy, so patients with Alzheimer's disease were notincluded in the studies.

The effects of vagus nerve stimulation on the cognition of animal modelsare given in experiments described in the following publications. Theanimal experiments show generally that it may be possible to promotecognition using vagus nerve stimulation, which suggests that failure inthe above-mentioned human experiments might be attributable to usingstimulation parameters that treat epilepsy or depression, instead ofparameters that preferentially enhance cognition. Vagus nervestimulation was shown to activate the locus ceruleus and to increasenorepinephrine output into the basolateral amygdala and hippocampus inrats [NARITOKU D K, Terry W J, Helfert R H. Regional induction of fosimmunoreactivity in the brain by anticonvulsant stimulation of the vagusnerve. Epilepsy Res 22(1,1995):53-62; HASSERT D L, Miyashita T, WilliamsC L. The effects of peripheral vagal nerve stimulation at amemory-modulating intensity on norepinephrine output in the basolateralamygdala. Behav Neurosci 118(1,2004):79-88; CHEN C C, Williams C L.Interactions between epinephrine, ascending vagal fibers, and centralnoradrenergic systems in modulating memory for emotionally arousingevents. Front Behav Neurosci 6:35. Epub 2012 Jun. 28, pp. 1-20].

In a rat model of traumatic brain injury, it was shown that vagus nervestimulation facilitated both the rate of recovery and the extent ofmotor and cognitive recovery [SMITH D C, Modglin A A, Roosevelt R W,Neese S L, Jensen R A, Browning R A, et al. Electrical stimulation ofthe vagus nerve enhances cognitive and motor recovery following moderatefluid percussion injury in the rat. J Neurotrauma22(12,2005):1485-1502]. Electrical stimulation of the vagus nerve (VNS)delivered at a moderate intensity following a learning experienceenhances memory in laboratory rats, while VNS at lower or higherintensities has little or no effect, which appears to involve modulatingsynaptic plasticity in the hippocampus [ZUO Y, Smith D C, Jensen R A.Vagus nerve stimulation potentiates hippocampal LTP in freely movingrats. Physiol Behav 90(4,2007):583-589]. More generally, vagus nervestimulation modulates norepinephrine levels via effects on the locusceruleus [DORR A E, Debonnel G. Effect of vagus nerve stimulation onserotonergic and noradrenergic transmission. J Pharmacol Exp Ther318(2,2006):890-898; MANTA S, Dong J, Debonnel G, Blier P. Enhancementof the function of rat serotonin and norepinephrine neurons by sustainedvagus nerve stimulation. J Psychiatry Neurosci 34(4,2009):272-80; SHENH, Fuchino Y, Miyamoto D, Nomura H, Matsuki N. Vagus nerve stimulationenhances perforant path-CA3 synaptic transmission via the activation ofβ-adrenergic receptors and the locus coeruleus. Int JNeuropsychopharmacol 15(4,2012):523-30].

Otherwise, the only mechanism by which vagus nerve stimulation has beensuggested to affect synaptic activity (e.g., seizures) is via its effecton cerebral circulation [HENRY T R, Bakay R A, Pennell P B, Epstein C M,Votaw J R. Brain blood-flow alterations induced by therapeutic vagusnerve stimulation in partial epilepsy: II. prolonged effects at high andlow levels of stimulation. Epilepsia 45(9,2004):1064-1070].

In a commonly assigned, co-pending patent application (Publication US20110152967, entitled Non-invasive treatment of neurodegenerativedisease, to SIMON et al), Applicants disclosed six novel mechanisms bywhich stimulation of the vagus nerve may be used to treat the underlyingpathophysiology of AD: (1) stimulate the vagus nerve in such a way as toenhance the availability or effectiveness of TGF-beta or otheranti-inflammatory cytokines; (2) stimulate the vagus nerve in such a wayas to enhance the availability or effectiveness of retinoic acid; (3)stimulate the vagus nerve in such a way as to promote the expression ofthe neurotrophic factors such as BDNF; (4) stimulate the vagus nerve tomodulate the capacity of TNF-alpha to function as a gliotransmitter,including modulating the activity of the cells between which TNF-relatedgliotransmission occurs; (5) stimulate the vagus nerve to modulate thedegradation of TNF-alpha, and/or modify the activity of existingTNF-alpha molecules as a pro-inflammatory mediator; and (6) stimulatethe vagus nerve in such a way as to suppress the release oreffectiveness of pro-inflammatory cytokines, through a mechanism that isdistinct from the one proposed by TRACEY and colleagues. Thus, patentsU.S. Pat. Nos. 6,610,713 and 6,838,471, entitled Inhibition ofinflammatory cytokine production by cholinergic agonists and vagus nervestimulation, to TRACEY, mention treatment of neurodegenerative diseaseswithin a long list of diseases, in connection with the treatment ofinflammation through stimulation of the vagus nerve. However, there isno mention or suggestion by TRACEY that his methods are intended tomodulate the activity of anti-inflammatory cytokines, and in fact, hisdisclosures disclaim a role for antiinflammatory cytokines as mediatorsof inflammation through stimulation of the vagus nerve.

SUMMARY OF THE INVENTION

The present invention involves devices and methods for theself-treatment of neurodegenerative diseases or disorders by a patientthrough electrical stimulation of one or more nerves within the patient.Devices are disclosed that allow the stimulation to be performednoninvasively, wherein electrodes are placed against the skin of thepatient.

In one aspect of the invention, electrical impulses are transmittedthrough an outer skin surface of the patient to the vagus nerve. Theelectrical impulses are sufficient to modify activity of the vagus nervesuch that inhibitory transmitters, such as norepinephrine (NE) andacetylcholine (Ach) are released in the brain. The disclosed inventiondoes not increase inhibitory neurotransmitters indiscriminatelythroughout the CNS, but instead preferentially increases the levels ofinhibitory neurotransmitters where it is needed, through selection ofappropriate vagus nerve stimulation parameters, which may be adjusted onan individualized basis and on the basis of progression of the disease.The release of these inhibitory neurotransmitters transition microglialcells in the brain from an M1 phenotype state (where they releasedestructive neurotoxins to kill a hypothetical invading organism) to anM2 phenotype state (where they are reparatory, phagocytosing dead cellsand releasing nerve growth factors). Thus, the neuroinflammation causedby the neurodegenerative disease or disorder is reduced or eliminated,thereby slowing or arresting the progression of the disease or disorder(for example, neuroinflammation directed against beta amyloid is aprimary driver of neuronal loss in Alzheimer's disease).

In another aspect of the invention, a nerve stimulation system comprisesa mobile phone that can be used for dual purposes: (1) as a phone, suchas a smartphone that would contain all of the typical features of such aphone (e.g., voice communication, Wi-Fi, web browsing, texting, emailconnectivity, etc.); and (2) as a nerve stimulation device incorporatedinto, or joined to and electrically connected with, the mobile phone.The nerve stimulation device preferably comprises one or more electrodesextending from an outer surface of the phone housing. The electrodes areconfigured to apply one or more electrical impulses through the surfaceof a patient's skin to a nerve within the patient, such as the vagusnerve. A signal generator is coupled to the electrodes for applying theelectrical impulses to the electrodes, and a power source is coupled tothe signal generator and/or the electrodes for providing power.

In one embodiment, the waveform of the signal that is to be applied tothe patient is first created in a device exterior to, and remote from,the mobile phone housing. The mobile phone preferably includes asoftware application that can be downloaded into the phone to receivethe waveform from the exterior device and then provide the electricalwaveform signal to the electrodes. In certain embodiments, the systemfurther includes an amplifier coupled to the electrodes to amplify thesignal generated by the application software and then apply theamplified signal to the electrodes. The amplifier may be incorporatedinto the phone, or joined to and connected to the phone, or it may be aseparate device that can be plugged into the phone to couple theamplifier with the software application and the electrodes. In oneembodiment, the amplifier includes a connector that connects to thespeaker output or the earphone jack socket in the mobile phone,amplifying a pseudo-audio stereo waveform signal that is produced by thesmartphone, and driving the electrodes with that signal.

The system is designed to address particular problems that arise duringself-treatment, when a medical professional is not present. Suchproblems include assuring that the patient stimulates a vagus nerve on aprescribed side of the neck (left or right), minimizing or documentingmotion of the stimulator, documenting the patient's adjustment of thestimulation amplitude, and controlling the amount of energy that can bedelivered to the patient during a stimulation session.

In one embodiment of the invention, the smartphone's rear camera is usedto image fluorescent spots that had been applied to reference positionson the patient's skin above the vagus nerve. During repeated sessions ofthe vagus nerve stimulation, the position and orientation of thestimulator are adjusted in such a way that fluorescent spots that areimaged by the camera appear in the same way during the successivesessions. Movement of the imaged fluorescent spots may also be used toassess the extent to which the stimulator is fluctuating in positionduring the course of a stimulation session.

The parameters for the protocol of each stimulation session may betransmitted from an external device to the stimulator device from aphysician-controlled computer, which provides authorization for therecharging of the stimulator device's batteries by a base station(typically a laptop computer). Parameters of the stimulation protocolmay be varied in response to heterogeneity in the symptoms of patients.Different stimulation parameters may also be selected as the course ofthe patient's medical condition changes. In preferred embodiments, thedisclosed stimulation methods and devices do not produce clinicallysignificant side effects, such as agitation or anxiety, or changes inheart rate or blood pressure.

In a preferred embodiment of the invention, the stimulator housingcomprises a rechargeable source of electrical power and two or moreelectrodes that are configured to stimulate a deep nerve. The stimulatormay comprise two electrodes that lie on both sides of the hand-heldstimulator housing. Each electrode may be in continuous contact with anelectrically conducting medium that extends from the patient-interfacestimulation element of the stimulator to the electrode. The interfaceelement contacts the patient's skin when the device is in operation.

Current passing through an electrode may be from about 0 to about 40 mA,with voltage across the electrodes being from about 0 to about 30 volts.The current is passed through the electrodes in bursts of pulses. Theremay be from about 1 to about 20 pulses per burst, preferably fivepulses. Each pulse within a burst has a duration from about 20 to about1000 microseconds, preferably about 200 microseconds. A burst followedby a silent inter-burst interval repeats from about 1 to about 5000bursts per second (bps, similar to Hz), preferably from about 15 toabout 50 bps, and even more preferably at about 25 bps. The preferredshape of each pulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodes,such that the electrodes produce an electric current and/or an electricfield within the patient. The electrical stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient from about 10 to about 600 V/m(preferably less than about 100 V/m) and an electrical field gradient ofgreater than about 2 V/m/mm. Electric fields that are produced at thevagus nerve are generally sufficient to excite all myelinated A and Bfibers, but not necessarily the unmyelinated C fibers. However, by usinga reduced amplitude of stimulation, excitation of A-delta and B fibersmay also be avoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

A method for treating a patient with a neurodegenerative diseaseaccording to the invention comprises generating an electrical signalsufficient to modulate a vagus nerve within the patient, wirelesslytransmitting the electric signal to a handheld stimulator, contacting anouter surface of a skin of the patient with a contact surface of thehandheld stimulator and applying one or more electrical impulses to theouter surface of the patient's skin such that the electrical impulsespass through the patient's skin transcutaneously to the vagus nerve. Theelectric impulses are sufficient to modulate the nerve and cause therelease of inhibitory neurotransmitters in the brain of the patient tocounteract neuroinflammation and slow or arrest the progression of theneurodegenerative disease.

In one embodiment, the method comprises a therapy regimen wherein thepatient applies the electrical stimulation therapy multiple times/day toprophylactically treat the disease. Each treatment preferably lasts fromabout 60 seconds to about 5 minutes. Applicant has discovered thatstimulation of the vagus nerve over a short period of time multipletimes per day can significantly improve a patient's neurodegenerativedisease over a period of time. In this manner, a continuous stimulationof the vagus nerve is not required to produce significant clinicalresults, such as those found with implantable vagal nerve stimulatorsthat continuously stimulate the vagus nerve about 24 hours/day. Thisdiscovery allows a patient to self-treat the neurodegenerative conditionwith a handheld non-invasive electrical stimulation device at home.

The novel systems, devices and methods for treating epilepsy are morecompletely described in the following detailed description of theinvention, with reference to the drawings provided herewith, and inclaims appended hereto. Other aspects, features, advantages, etc. willbecome apparent to one skilled in the art when the description of theinvention herein is taken in conjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference. If anydisclosures are incorporated herein by reference and such disclosuresconflict in part and/or in whole with the present disclosure, then tothe extent of conflict, and/or broader disclosure, and/or broaderdefinition of terms, the present disclosure controls. If suchdisclosures conflict in part and/or in whole with one another, then tothe extent of conflict, the later-dated disclosure controls.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A shows structures within a patient's nervous system that may bemodulated by electrical stimulation of a vagus nerve.

FIG. 1B shows functional networks within the brain (resting statenetworks) that may be modulated by electrical stimulation of a vagusnerve.

FIG. 1C shows a schematic view of nerve modulating devices according tothe present invention, which supply controlled pulses of electricalcurrent to surface electrodes.

FIG. 2A shows an exemplary electrical voltage/current profile forstimulating and/or modulating impulses that are applied to a nerveaccording to the present invention; FIG. 2B illustrates an exemplarybursting electrical waveform for stimulating and/or modulating a nerveaccording to the present invention; and FIG. 2C illustrates twosuccessive bursts of the waveform of FIG. 2B.

FIG. 3A is a front view of a dual-electrode stimulator according to anembodiment of the present invention, showing that the stimulator devicecomprises a smartphone; FIG. 3B is a back view of the dual-electrodestimulator shown in FIG. 3A; and FIG. 3C is a side view of thedual-electrode stimulator shown in FIG. 3A.

FIG. 4A illustrates an exploded view of an electrode assembly accordingto one embodiment of the present invention; and FIG. 4B illustrates anassembled view of the electrode assembly shown in FIG. 4A.

FIG. 5A illustrates a cross-sectional view of an optical assembly usedto shift illumination of a smartphone flash LED from visible to infraredlight and to use that infrared light to excite and image fluorescencefrom material placed in the patient's skin; FIG. 5B illustrates across-sectional view of an optical assembly used to excite and imagefluorescence from material placed in the patient's skin, when theshifting of the wavelength of LED light is not needed; and FIG. 5Crotates the view shown in FIG. 5A by 90 degrees, showing where theoptical assembly is snapped into the stimulator between the electrodesurfaces.

FIG. 6 shows how a continuously imaged fluorescence image of two spotsis superimposed onto a reference image of those spots, in order tooptimally position the stimulator.

FIG. 7 shows an expanded diagram of the control unit shown in FIG. 1,separating components of the control unit into those within the housingof the stimulator, those within a base station, and those withinsmartphone and internet-based devices, also showing communication pathsbetween such components.

FIG. 8 illustrates the approximate position of the stimulator accordingone embodiment of the present invention, when used to stimulate theright vagus nerve in the neck of an adult patient.

FIG. 9 illustrates the approximate position of the stimulator accordingone embodiment of the present invention, when used to stimulate theright vagus nerve in the neck of a child who wears a collar to hold thestimulator.

FIG. 10 illustrates the stimulator according one embodiment of thepresent invention, when positioned to stimulate a vagus nerve in thepatient's neck, wherein the stimulator is applied to the surface of theneck in the vicinity of the identified anatomical structures.

FIG. 11 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, electrodes applied to the skin of the patientgenerate currents within the tissue of the patient. An objective of oneembodiment of the invention is to produce and apply the electricalimpulses so as to interact with the signals of one or more nerves, inorder to achieve the therapeutic result. Much of the disclosure will bedirected specifically to treatment of a patient by stimulation in oraround a vagus nerve, with devices positioned non-invasively on or neara patient's neck to treat neurodegenerative diseases, such as such asdementia, Alzheimer's disease, ischemic stroke, post-traumaticconcussion, chronic traumatic encephalopathy and the like.

As discussed in more detail below, electrical impulses are transmittedthrough an outer skin surface of the patient to the vagus nerve. Theelectrical impulses are sufficient to modify activity of the vagus nervesuch that inhibitory transmitters, such as norepinephrine (NE) andacetylcholine (Ach) are released in the brain. The disclosed inventiondoes not increase inhibitory neurotransmitters indiscriminatelythroughout the CNS, but instead preferentially increases the levels ofinhibitory neurotransmitters where it is needed, through selection ofappropriate vagus nerve stimulation parameters, which may be adjusted onan individualized basis and on the basis of progression of the disease.The release of these inhibitory neurotransmitters transition microglialcells in the brain from an M1 phenotype state (where they releasedestructive neurotoxins to kill a hypothetical invading organism) to anM2 phenotype state (where they are reparatory, phagocytosing dead cellsand releasing nerve growth factors). Thus, the neuroinflammation causedby the neurodegenerative disease or disorder is reduced or eliminated,thereby slowing or arresting the progression of the disease or disorder.

With respect to Alzheimer's disease (AD), a novel mechanism of actionfor benefiting AD patients, as well as patients with a precursor of AD(e.g., mild cognitive impairment), is based on the use of vagus nervestimulation to induce the release of increased quantities ofnorepinephrine from projections of a patient's locus ceruleus.Norepinephrine is known to strongly suppress neuroinflammation in thecentral nervous system (CNS), and neuroinflammation directed againstbeta amyloid is a primary driver of neuronal loss in AD. According tothe invention, normal levels of norepinephrine in the CNS maintain atolerance of beta amyloid, which is also present in without AD.

However, in AD, the terminal fields of norepinephrine-releasing locusceruleus cells that innervate those brain regions containing betaamyloid become damaged or destroyed, which then leads to the perikaryalloss of those locus ceruleus cells (Wallerian-like degeneration). Lossof locus ceruleus cells, and loss of the protective norepinephrine thatthey produce, triggers an increased release of pro-inflammatory cytokineand cytotoxic agents by microglial cells against decreasingly toleratedbeta amyloid aggregates. This results in further damage to, and loss of,locus ceruleus terminal fields and the norepinephrine that they produce,as well as damage to or loss of other nearby nerve cells. The result isa vicious cycle in which both the protective locus ceruleus cells andbeta amyloid-containing regions of the brain die. The present inventionbreaks this vicious cycle by using vagus nerve stimulation to induce therelease of larger quantities of norepinephrine from projections of apatient's locus ceruleus. Thus, maintaining norepinephrine release ashigh as possible may disrupt this degenerative cycle by transitioningthe microglial cells from M1 destructive states to M2 reparative states,thereby reducing neuroinflammation and halting or slowing theprogression of the disease and protecting the locus ceruleus itself.

The progression of AD can be monitored through the use of biomarkers. Apre-symptomatic phase occurs first, in which individuals are cognitivelynormal but some have AD pathological changes. This is followed by asecond prodromal phase of AD, commonly referred to as mild cognitiveimpairment (MCI). The final phase of AD is true dementia. Methods of theinvention may be applied to patients in any of these stages. For mostpatients, the stimulation may be performed for 30 minutes, and thetreatment is performed once a week for 12 weeks or longer, because theprogression of the disease from prodrome to true dementia is a chronicsituation. Alternatively, stimulation may be performed only whenpatients are attempting to learn important information. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the pathophysiology of patients. Differentstimulation parameters may also be selected as the course of thepatient's disease changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

Post-concussion syndrome (PCS) is a set of symptoms that may continuefor weeks, months, or occasionally a year or more after a concussion.PCS may cause a mild form of traumatic brain injury (TBI). The rates ofPCS vary, but most studies report that about 15% of individuals with ahistory of a single mild TBI develop persistent symptoms associated withthe injury. A diagnosis may be made when symptoms resulting fromconcussion last for more than three months after the injury. Thecondition is associated with a wide range of symptoms: physical, such asheadache; cognitive, such as difficulty concentrating; and emotional andbehavioral, such as irritability. Headaches that occur after aconcussion may feel like migraine or tension-type headaches. Mostheadaches are tension-type headaches, which may be associated with aneck injury that occurred at the same time of the head injury. Thoughthere is no treatment for PCS, symptoms can be treated; medications andphysical and behavioral therapy may be used, and individuals can beeducated about symptoms and provided with the expectation of recovery.The majority of PCS cases resolve after a period of time.

Chronic traumatic encephalopathy (CTE) is a form of encephalopathy thatis a progressive degenerative disease, which can currently only bedefinitively diagnosed postmortem, in individuals with a history ofmultiple concussions and other forms of head injury. The disease waspreviously called dementia pugilistica (DP), as it was initially foundin those with a history of boxing. CTE has been most commonly found inprofessional athletes participating in football, soccer, ice hockey,rugby, professional wrestling and other contact sports who haveexperienced repetitive brain trauma. It has also been found in soldiersexposed to a blast or a concussive injury, in both cases resulting incharacteristic degeneration of brain tissue and the accumulation of tauprotein. Individuals with CTE may show symptoms of dementia, such asmemory loss, aggression, confusion and depression, which generallyappear years or many decades after the trauma.

Similar to the treatment of D, the present invention provides methodsand devices for the treatment of concussion, such as post-concussionsyndrome, CTE and other forms of concussions. Stimulation of the vagusnerve increases the release of inhibitory neurotransmitters in thebrain, which modify the glial cells such that they become reparative(M2), rather than destructive (M1). This slows or completely halts thedegenerative process that may occur after a patient has suffered one ormore concussions.

A stroke is the acute loss of brain function due to loss of normal bloodsupply to the brain or brainstem, spinal cord, or retina. This can bedue to the lack of blood flow (ischemia) caused by blockage of a bloodvessel due to thrombosis or arterial embolism. Stroke may also be due toa hemorrhage. A thrombotic stroke occurs when a blood clot (thrombus)forms in one of the brain's arteries, which may be formed in thevicinity of fatty deposits (plaque) that build up in the artery to causereduced blood flow (atherosclerosis). Less commonly, the thrombus mayform at the site of a vasospasm of a migraine sufferer. A thrombus canblock a large brain artery (causing widespread brain damage) or a smallartery, the latter resulting in a so-called lacunar stroke. An embolicstroke occurs when a blood clot or other debris (embolus) forms outsidebrain, for example in an atrium of the patient's heart, and istransported through the bloodstream to lodge in an artery of the brain.About half to two-thirds of all strokes are thrombotic strokes.

Ischemic stroke occurs in 87% of stroke patients and may be eithersymptomatic or silent. Symptomatic ischemic strokes are manifest byclinical signs of focal or global cerebral, spinal, or retinaldysfunction caused by death of neural tissue (central nervous systeminfarction). A silent stroke is a documented central nervous systeminfarction (tissue death due to lack of oxygen) that was asymptomatic.Symptomatic ischemic strokes are usually treated with thrombolyticagents (“clot busters”), preferably within three hours of the onset ofthe stroke. In contrast, hemorrhagic strokes occur in 13% of strokepatients, who may be treated by neurosurgery. Hemorrhagic strokesinclude bleeding within the brain (intracerebral hemorrhage) andbleeding between the inner and outer layers of the tissue covering thebrain (subarachnoid hemorrhage).

A transient ischemic attack (TIA) is also caused by ischemia in thebrain, spinal cord or retina. TIAs share the same underlying etiology asischemic strokes and produce the same symptoms, such as contralateralparalysis, sudden weakness or numbness, dimming or loss of vision,aphasia, slurred speech and mental confusion. Unlike a stroke, thesymptoms of a TIA can resolve typically within a day, whereas thesymptoms from a stroke can persist due to death of neural tissue (acuteinfarction). Thus, a transient ischemic attack may be defined as atransient episode of neurological dysfunction caused by focal brain,spinal cord, or retinal ischemia, without acute infarction [EASTON J D,Saver J L, Albers G W, et al. Definition and evaluation of transientischemic attack: a scientific statement for healthcare professionalsfrom the American Heart Association/American Stroke Association StrokeCouncil et al. Stroke 40(6,2009):2276-2293; PRABHAKARAN S. Reversiblebrain ischemia: lessons from transient ischemic attack. Curr Opin Neurol20(1,2007):65-70].

A stroke causes an infarct, which comprises irreversibly dead or dyingneuronal tissue that has been deprived of oxygen. The infarct issurrounded by a penumbra of ischemic tissue, which is salvagable withprompt restoration of oxygen through blood perfusion. Therefore, promptdiagnosis and treatment of the stroke patient can be essential in orderto save as much of the penumbra tissue as possible, thereby saving theneuronal functions that are performed by that salvagable tissue.Ischemic stroke is generally painless, and the patient usually remainsconscious during the diagnosis. Neurological symptoms that are exhibitedby the patient upon interrogation and examination are used to make apreliminary evaluation as to whether a stroke has occurred.

The present invention discloses stimulation of the cervical vagus nerveas a method for helping the stroke patient recover motor skills duringrehabilitation The present invention also discloses use of noninvasivenerve stimulation for the rehabilitative treatment of conditions otherthan motor deficits in stroke patients. In particular, noninvasive vagusnerve stimulation may be used to treat a condition known as spatialneglect, also known as hemispatial neglect, hemiagnosia, hemineglect,unilateral neglect, unilateral visual inattention, hemi-inattention orneglect syndrome. It is said to occur in approximately 25-30% of allstroke-affected individuals, although some estimates place the frequencyas high as 90% [RINGMAN J M, Saver J L, Woolson R F, Clarke W R, Adams HP. Frequency, risk factors, anatomy, and course of unilateral neglect inan acute stroke cohort. Neurology 63(3,2004):468-474; BUXBAUM L J,Ferraro M K, Veramonti T, Farne A, Whyte J, Ladavas E, Frassinetti F,Coslett H B. Hemispatial neglect: Subtypes, neuroanatomy, anddisability. Neurology 62(5,2004):749-756; KLEINMAN J T, Newhart M, DavisC, Heidler-Gary J, Gottesman R F, Hillis A E. Right hemispatial neglect:frequency and characterization following acute left hemisphere stroke.Brain Cogn 64(1,2007):50-59]. Spatial neglect occurs in stroke patientsof all ages, including children [LAURENT-VANNIER A, Pradat-Diehl P,Chevignard M, Abada G, De Agostini M. Spatial and motor neglect inchildren. Neurology 60(2,2003):202-207].

In one aspect of the invention, noninvasive vagus nerve stimulation maybe used as a neuroprotective therapy during acute stroke, e.g., byacting in opposition to glutamate-mediated excitation of nerve tissue,through the inhibitory effects of GABA, and/or serotonin, and/ornorepinephrine that are released from the periaqueductal gray, raphenucei, and locus coeruleus, respectively. In other aspects of theinvention, vagus nerve stimulation is used to modify glial cells in thebrain to transition those cells from M1 to M2 states, as discussedabove.

A vagus nerve stimulation treatment according to the present inventionis conducted for thirty seconds to five minutes, preferably about 90seconds to three minutes and more preferably about two minutes (eachdefined as a single dose). For prophylactic treatments, such as atreatment to avert a stroke or transient ischemic attack, the therapypreferably comprises multiple doses/day over a period of time that maylast from one week to a number of years. In certain embodiments, thetreatment will comprise multiple doses at predetermined times during theday and/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3 singledoses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin when an imminent stroke or TIA is forecasted, or in a risk-factorreduction program it may be performed throughout the day beginning afterthe patient arises in the morning. In some embodiments, a method fortreating a patient with a neurodegenerative disease, as disclosedherein, comprises: generating an electric signal; wirelesslytransmitting the electric signal to a mobile phone hosting a handheldstimulator including a contact surface; contacting an outer surface of askin of the patient with the contact surface; and applying, as thecontact surface contacts the outer surface, an electrical impulse,formed based on the electric signal, from the contact surface to theouter surface such that the electrical impulse passes transcutaneouslythrough the skin to a vagus nerve within a body of the patient, whereinthe electrical impulse is sufficient to modulate the vagus nerve andthereby modify the neurodegenerative disease. Further, in someembodiments, the method can further comprise prophylactically treatingthe neurodegenerative disease with a treatment regimen, wherein thetreatment regimen comprises continuously applying the electrical impulsefor a time period from about 30 seconds to about 300 seconds as a singledose and wherein the treatment regimen comprises applying a single doseon a daily basis. Moreover, in some embodiments, the treatment regimencan comprise applying from 2 to 5 single doses per day.

For an acute treatment, such as treatment of acute stroke, the therapymay consist of: (1) 1 treatment at the onset of symptoms; (2) 1treatment at the onset of symptoms, followed by another treatment at5-15 min; or (3) 1 treatment every hour.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient and/or PCS, the therapymay consist of: (1) 3 treatments/day; (2) 2 treatments, eitherconsecutively or separated by 5 min, 3×/day; (3) 3 treatments, eitherconsecutively or separated by 5 min, 2×/day; (4) 2 or 3 treatments,either consecutively or separated by 5 min, up to 10×/day; or (5) 1, 2or 3 treatments, either consecutively or separated by 5 min, every 15,30, 60 or 120 min. In an exemplary embodiment, each treatment sessioncomprises 1-3 doses administered to the patient either consecutively orseparated by 5 minutes. The treatment sessions are administered every15, 30, 60 or 120 minutes during the day such that the patient couldreceive 2 doses every hour throughout a 24 hour day.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or concussionthat occur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

Although the present invention is particularly focused on the treatmentof neurodegenerative disorders, it should be appreciated that the nervestimulation may also result in other benefits to the patient such as:relaxation of the smooth muscle of the bronchia for treatment ofbronchoconstriction associated with asthma, COPD and/orexercised-induced bronchoconstriction, increase in blood pressureassociated with orthostatic hypotension, reduction in blood pressurethat may be associated with, for example, refractory hypertension,treating ileus conditions, neuropsychiatric disorders, such asdepression, anxiety and/or personality disorders, anaphylaxis, obesityand/or type II diabetes, seizures, such as epileptic seizures, migraine,tension-type, cluster, MOH and other types of headache, rhinitis,sinusitis, atrial fibrillation, autism, modulation of liver function,gastroparesis and other functional gastrointestinal disorders, movementdisorders, CHF, chronic pain, fibromyalgia, metabolic or thyroiddisorders, cardiovascular disease, and/or any other ailment that may beaffected by nerve transmissions of a vagus nerve. Such treatments fordifferent disorders are disclosed in the following US patentapplications assigned to ElectroCore, LLC (the complete disclosures ofwhich are incorporated by reference in their entirety for all purposes):U.S. patent application Ser. No. 13/858,114, filed Apr. 8, 2013(ELEC-47), U.S. patent application Ser. No. 13/783,391, filed Mar. 3,2013 (ELEC-49), U.S. patent application Ser. No. 13/736,096, filed Jan.8, 2013 (ELEC-43), U.S. patent application Ser. No. 13/731,035, filedDec. 30, 2012 (ELEC-46), U.S. patent application Ser. No. 13/603,799filed Sep. 5, 2012 (ELEC-44-1), U.S. patent application Ser. No.13/357,010, filed Jan. 24, 2012 (ELEC-41), U.S. patent application Ser.No. 13/279,437 filed Oct. 24, 2011 (ELEC-40), U.S. patent applicationSer. No. 13/222,087 filed Aug. 31, 2011 (ELEC-39), U.S. patentapplication Ser. No. 13/183,765 filed Jul. 15, 2011 (ELEC-38), U.S.patent application Ser. No. 13/183,721 filed Jul. 15, 2011, now U.S.Pat. No. 8,676,330 issued Mar. 18, 2014 (ELEC-36), U.S. patentapplication Ser. No. 13/109,250 filed May 17, 2011, now U.S. Pat. No.8,676,324 issued Mar. 18, 2014 (ELEC-37), U.S. patent application Ser.No. 13/075,746 filed Mar. 30, 2011 (ELEC-35), U.S. patent applicationSer. No. 13/024,727, filed Feb. 10, 2011 (ELEC-34), U.S. patentapplication Ser. No. 13/005,005 filed Jan. 12, 2011 (ELEC-33), U.S.patent application Ser. No. 12/964,050 filed Dec. 9, 2010 (ELEC-32),U.S. patent application Ser. No. 12/859,568 filed Aug. 9, 2010(ELEC-31), U.S. patent application Ser. No. 12/408,131 filed Mar. 20,2009 (ELEC-17CP1) and U.S. patent application Ser. No. 12/612,177 filedNov. 9, 2009 now U.S. Pat. No. 8,041,428 issued Oct. 18, 2011(ELEC-14CP1).

It will also be appreciated that the devices and methods of the presentinvention can be applied to other tissues and nerves of the body,including but not limited to other parasympathetic nerves, sympatheticnerves, spinal or cranial nerves. In one embodiment, the devices of thepresent invention are applied to the trigeminal nerve to treat a varietyof medical disorders, including but not limited to headache, such asmigraine, tension type headache, chronic headache and/or occipitalneuralgia. In this embodiment, the devices described below are placedagainst the patient's forehead and electrical impulses are appliedtranscutaneously through the patient's skin to the supratrochear and/orsupraorbital branches of the trigeminal nerve sufficient to stimulatethe nerve and relieve pain associated with headache. Such treatments ofthese conditions are described more fully in the followingpatents/patent applications (the complete disclosures of which arehereby incorporated by reference in their entirety for all purposes): USPatent Publication Numbers 2013/0282095, 2009/0210028, 2007/0276451 andU.S. Pat. No. 8,428,734.

The fact that electrical stimulation of a vagus nerve can be used totreat so many disorders may be understood as follows. The vagus nerve iscomposed of motor and sensory fibers. The vagus nerve leaves thecranium, passes down the neck within the carotid sheath to the root ofthe neck, then passes to the chest and abdomen, where it contributes tothe innervation of the viscera. A human vagus nerve (tenth cranialnerve, paired left and right) consists of over 100,000 nerve fibers(axons), mostly organized into groups. The groups are contained withinfascicles of varying sizes, which branch and converge along the nerve.Under normal physiological conditions, each fiber conducts electricalimpulses only in one direction, which is defined to be the orthodromicdirection, and which is opposite the antidromic direction. However,external electrical stimulation of the nerve may produce actionpotentials that propagate in orthodromic and antidromic directions.Besides efferent output fibers that convey signals to the various organsin the body from the central nervous system, the vagus nerve conveyssensory (afferent) information about the state of the body's organs backto the central nervous system. Some 80-90% of the nerve fibers in thevagus nerve are afferent (sensory) nerves, communicating the state ofthe viscera to the central nervous system.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia, which take the form of swellingsnear the base of the skull. Vagal afferents traverse the brainstem inthe solitary tract, with some eighty percent of the terminating synapsesbeing located in the nucleus of the tractus solitarius (or nucleustractus solitarii, nucleus tractus solitarius, or NTS). The NTS projectsto a wide variety of structures in the central nervous system, such asthe amygdala, raphe nuclei, periaqueductal gray, nucleusparagigantocellurlais, olfactory tubercule, locus ceruleus, nucleusambiguus and the hypothalamus. The NTS also projects to the parabrachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insula, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions [JEAN A. The nucleustractus solitarius: neuroanatomic, neurochemical and functional aspects.Arch Int Physiol Biochim Biophys 99(5,1991): A3-A52]. Thus, stimulationof vagal afferents can modulate the activity of many structures of thebrain and brainstem through these projections.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections controls parasympathetic function primarilybelow the level of the diaphragm, while the ventral vagal complex,comprised of nucleus ambiguus and nucleus retrofacial, controlsfunctions primarily above the diaphragm in organs such as the heart,thymus and lungs, as well as other glands and tissues of the neck andupper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus, which is relevant to potential cardiovascular sideeffects that may be produced by vagus nerve stimulation.

The vagus efferent fibers innervate parasympathetic ganglionic neuronsthat are located in or adjacent to each target organ. The vagalparasympathetic tone resulting from the activity of these fibers isbalanced reflexively in part by sympathetic innervations. Consequently,electrical stimulation of a vagus nerve may result not only inmodulation of parasympathetic activity in postganglionic nerve fibers,but also a reflex modulation of sympathetic activity. The ability of avagus nerve to bring about widespread changes in autonomic activity,either directly through modulation of vagal efferent nerves, orindirectly via activation of brainstem and brain functions that arebrought about by electrical stimulation of vagal afferent nerves,accounts for the fact that vagus nerve stimulation can treat manydifferent medical conditions in many end organs. Selective treatment ofparticular conditions is possible because the parameters of theelectrical stimulation (frequency, amplitude, pulse width, etc.) mayselectively activate or modulate the activity of particular afferent orefferent A, B, and/or C fibers that result in a particular physiologicalresponse in each individual.

As ordinarily practiced, the electrodes used to stimulate a vagus nerveare implanted about the nerve during open neck surgery. For manypatients, this may be done with the objective of implanting permanentelectrodes to treat epilepsy, depression, or other conditions [Arun PaulAMAR, Michael L. Levy, Charles Y. Liu and Michael L. J. Apuzzo. Chapter50. Vagus nerve stimulation. pp. 625-638, particularly 634-635. In:Elliot S. Krames, P. Hunber Peckham, Ali R. Rezai, eds. Neuromodulation.London: Academic Press, 2009; KIRSE D J, Werle A H, Murphy J V, Eyen TP, Bruegger D E, Hornig G W, Torkelson R D. Vagus nerve stimulatorimplantation in children. Arch Otolaryngol Head Neck Surg128(11,2002):1263-1268]. In that case, the electrode is often a spiralelectrode, although other designs may be used as well [U.S. Pat. No.4,979,511, entitled Strain relief tether for implantable electrode, toTERRY, Jr.; U.S. Pat. No. 5,095,905, entitled Implantable neuralelectrode, to KLEPINSKI]. In other patients, a vagus nerve iselectrically stimulated during open-neck thyroid surgery in order toconfirm that the nerve has not been accidentally damaged during thesurgery. In that case, a vagus nerve in the neck is surgically exposed,and a temporary stimulation electrode is clipped about the nerve[SCHNEIDER R, Randolph G W, Sekulla C, Phelan E, Thanh P N, Bucher M,Machens A, Dralle H, Lorenz K. Continuous intraoperative vagus nervestimulation for identification of imminent recurrent laryngeal nerveinjury. Head Neck. 2012 Nov. 20. doi: 10.1002/hed.23187 (Epub ahead ofprint, pp. 1-8)].

It is also possible to electrically stimulate a vagus nerve using aminimally invasive surgical approach, namely percutaneous nervestimulation. In that procedure, a pair of electrodes (an active and areturn electrode) are introduced through the skin of a patient's neck tothe vicinity of a vagus nerve, and wires connected to the electrodesextend out of the patient's skin to a pulse generator [Publicationnumber US20100241188, entitled Percutaneous electrical treatment oftissue, to J. P. ERRICO et al.; SEPULVEDA P, Bohill G, Hoffmann T J.Treatment of asthmatic bronchoconstriction by percutaneous low voltagevagal nerve stimulation: case report. Internet J Asthma Allergy Immunol7(2009):e1 (pp 1-6); MINER, J. R., Lewis, L. M., Mosnaim, G. S., Varon,J., Theodoro, D. Hoffman, T. J. Feasibility of percutaneous vagus nervestimulation for the treatment of acute asthma exacerbations. Acad EmergMed 2012; 19: 421-429], the complete disclosures of which areincorporated herein by reference in their entirety for all purposes.

Percutaneous nerve stimulation procedures had previously been describedprimarily for the treatment of pain, but not for a vagus nerve, which isordinarily not considered to produce pain and which presents specialchallenges [HUNTOON M A, Hoelzer B C, Burgher A H, Hurdle M F, Huntoon EA. Feasibility of ultrasound-guided percutaneous placement of peripheralnerve stimulation electrodes and anchoring during simulated movement:part two, upper extremity. Reg Anesth Pain Med 33(6,2008):558-565; CHANI, Brown A R, Park K, Winfree C J. Ultrasound-guided, percutaneousperipheral nerve stimulation: technical note. Neurosurgery 67(3 SupplOperative, 2010):ons136-139; MONTI E. Peripheral nerve stimulation: apercutaneous minimally invasive approach. Neuromodulation7(3,2004):193-196; Konstantin V SLAVIN. Peripheral nerve stimulation forneuropathic pain. US Neurology 7(2,2011):144-148].

In one embodiment, the stimulation device is introduced through apercutaneous penetration in the patient to a target location within,adjacent to, or in close proximity with, the carotid sheath thatcontains the vagus nerve. Once in position, electrical impulses areapplied through the electrodes of the stimulation device to one or moreselected nerves (e.g., vagus nerve or one of its branches) to stimulate,block or otherwise modulate the nerve(s) and treat the patient'scondition or a symptom of that condition. For some conditions, thetreatment may be acute, meaning that the electrical impulse immediatelybegins to interact with one or more nerves to produce a response in thepatient. In some cases, the electrical impulse will produce a responsein the nerve(s) to improve the patient's condition or symptom in lessthan 3 hours, preferably less than 1 hour and more preferably less than15 minutes. For other conditions, intermittently scheduled or as-neededstimulation of the nerve may produce improvements in the patient overthe course of several days, weeks, months or years. A more completedescription of a suitable percutaneous procedure for vagal nervestimulation can be found in commonly assigned, co-pending U.S. patentapplication titled “Percutaneous Electrical Treatment of Tissue”, filedApr. 13, 2009 (Ser. No. 12/422,483), the complete disclosure of which ishereby incorporated by reference in its entirety for all purposes.

In another embodiment of the invention, a time-varying magnetic field,originating and confined to the outside of a patient, generates anelectromagnetic field and/or induces eddy currents within tissue of thepatient. In another embodiment, electrodes applied to the skin of thepatient generate currents within the tissue of the patient. An objectiveof one embodiment of the invention is to produce and apply theelectrical impulses so as to interact with the signals of one or morenerves, in order to prevent or avert a stroke and/or transient ischemicattack, to ameliorate or limit the effects of an acute stroke ortransient ischemic attack, and/or to rehabilitate a stroke patient.

FIG. 1A shows the location of the stimulation as “Vagus NerveStimulation,” relative to its connections with other anatomicalstructures that are potentially affected by the stimulation. Indifferent embodiments of the invention, various brain and brainstemstructures are preferentially modulated by the stimulation. Thesestructures will be described in sections of the disclosure that follow,along with the rationale for modulating their activity as a prophylaxisor treatment for stroke or transient ischemic attack. As a preliminarymatter, we first describe the vagus nerve itself and its most proximalconnections, which are particularly relevant to the disclosure below ofthe electrical waveforms that are used to perform the stimulation.

The vagus nerve (tenth cranial nerve, paired left and right) is composedof motor and sensory fibers. The vagus nerve leaves the cranium, passesdown the neck within the carotid sheath to the root of the neck, thenpasses to the chest and abdomen, where it contributes to the innervationof the viscera.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system. Propagation of electrical signals in efferentand afferent directions is indicated by arrows in FIG. 1A. Ifcommunication between structures is bidirectional, this is shown in FIG.1A as a single connection with two arrows, rather than showing theefferent and afferent nerve fibers separately.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths. It is understood that the anatomy ofthe vagus nerve is developing in newborns and infants, which accounts inpart for the maturation of autonomic reflexes. Accordingly, it is alsounderstood that the parameters of vagus nerve stimulation in the presentinvention are chosen in such a way as to account for this age-relatedmaturation [PEREYRA P M, Zhang W, Schmidt M, Becker L E. Development ofmyelinated and unmyelinated fibers of human vagus nerve during the firstyear of life. J Neurol Sci 110(1-2,1992):107-113; SCHECHTMAN V L, HarperR M, Kluge K A. Development of heart rate variation over the first 6months of life in normal infants. Pediatr Res 26(4,1989):343-346].

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1A). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra.

Vagal afferents traverse the brainstem in the solitary tract, with someeighty percent of the terminating synapses being located in the nucleusof the tractus solitarius (or nucleus tractus solitarii, nucleus tractussolitarius, or NTS, see FIG. 1A). The NTS projects to a wide variety ofstructures in the central nervous system, such as the amygdala, raphenuclei, periaqueductal gray, nucleus paragigantocellurlais, olfactorytubercule, locus ceruleus, nucleus ambiguus and the hypothalamus. TheNTS also projects to the parabrachial nucleus, which in turn projects tothe hypothalamus, the thalamus, the amygdala, the anterior insula, andinfralimbic cortex, lateral prefrontal cortex, and other corticalregions [JEAN A. The nucleus tractus solitarius: neuroanatomic,neurochemical and functional aspects. Arch Int Physiol Biochim Biophys99(5,1991):A3-A52]. Such central projections are discussed below inconnection with the interoception and resting state neural networks.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections (see FIG. 1A), controls parasympatheticfunction primarily below the level of the diaphragm (e.g. gut and itsenterochromaffin cells), while the ventral vagal complex, comprised ofnucleus ambiguus and nucleus retrofacial, controls functions primarilyabove the diaphragm in organs such as the heart, thymus and lungs, aswell as other glands and tissues of the neck and upper chest, andspecialized muscles such as those of the esophageal complex. Forexample, the cell bodies for the preganglionic parasympathetic vagalneurons that innervate the heart reside in the nucleus ambiguus, whichis relevant to potential cardiovascular side effects that may beproduced by vagus nerve stimulation.

Broadly speaking, applicant has determined that there are threecomponents to the effects of nVNS on the brain. The strongest effectoccurs during the two minute stimulation and results in significantchanges in brain function that can be clearly seen as acute changes inautonomic function (e.g. measured using pupillometry, heart ratevariability, galvanic skin response, or evoked potential) and activationand inhibition of various brain regions as shown in fMRI imagingstudies. The second effect, of moderate intensity, lasts for 15 to 180minutes after stimulation. Animal studies have shown changes inneurotransmitter levels in various parts of the brain that persist forseveral hours. The third effect, of mild intensity, lasts up to 8 hoursand is responsible for the long lasting alleviation of symptoms seenclinically and, for example, in animal models of migraine headache.

Thus, depending on the medical indication, whether it is a chronic oracute treatment, and the natural history of the disease, differenttreatment protocols may be used. In particular, applicant has discoveredthat it is not necessary to “continuously stimulate” the vagus nerve (orto in order to provide clinically efficacious benefits to patients withcertain neurodegenerative disorders). The term “continuously stimulate”as defined herein means stimulation that follows a certain On/Offpattern continuously 24 hours/day. For example, existing implantablevagal nerve stimulators “continuously stimulate” the vagus nerve with apattern of 30 seconds ON/5 minutes OFF (or the like) for 24 hours/dayand seven days/week. Applicant has determined that this continuousstimulation is not necessary to provide the desired clinical benefit.For example, in the treatment of Alzheimer's and/or PCS, three 2-minutestimulations three times per day appear to be optimal. Sometimes,multiple consecutive, two minute stimulations are required. Thus, theinitial treatment protocol corresponds to what may be optimum for thepopulation of patients at large for a given condition. However, thetreatment may then be modified on an individualized basis, depending onthe response of each particular patient.

The present invention contemplates three types of interventionsinvolving stimulation of a vagus nerve: prophylactic, acute andcompensatory (rehabilitative). Among these, the acute treatment involvesthe fewest administrations of vagus nerve stimulations, which begin uponthe appearance of symptoms. It is intended primarily to enlist andengage the autonomic nervous system to inhibit excitatoryneurotransmissions that accompany the symptoms. The prophylactictreatment resembles the acute treatment in the sense that it isadministered as though acute symptoms had just occurred (even thoughthey have not) and is repeated at regular intervals, as though thesymptoms were reoccurring (even though they are not). The rehabilitativeor compensatory treatments, on the other hand, seek to promote long-termadjustments in the central nervous system, compensating for deficienciesthat arose as the result of the patient's disease by making new neuralcircuits.

A vagus nerve stimulation treatment according to the present inventionis conducted for continuous period of thirty seconds to five minutes,preferably about 90 seconds to about three minutes and more preferablyabout two minutes (each defined as a single dose). After a dose has beencompleted, the therapy is stopped for a period of time (depending on thetreatment as described below). For prophylactic treatments, the therapypreferably comprises multiple doses/day over a period of time that maylast from one week to a number of years. In certain embodiments, thetreatment will comprise multiple doses at predetermined times during theday and/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3doses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin when the patient experiences an acute symptom, such as a headachefrom PCS, or in a risk factor reduction program it may be performedthroughout the day beginning after the patient arises in the morning.

In an exemplary embodiment, each treatment session comprises 1-3 dosesadministered to the patient either consecutively or separated by 5minutes. The treatment sessions are administered every 15, 30, 60 or 120minutes during the day such that the patient could receive 2 doses everyhour throughout a 24-hour day.

For certain disorders, the time of day can be more important than thetime interval between treatments. For example, the locus correleus hasperiods of time during a 24-hour day wherein it has inactive periods andactive periods. Typically, the inactive periods can occur in the lateafternoon or in the middle of the night when the patient is asleep. Itis during the inactive periods that the levels of inhibitoryneurotransmitters in the brain that are generated by the locus correleusare reduced. This may have an impact on certain disorders. For example,patients suffering from headaches caused by PCS or chronic traumaticencephalopathy often receive these headaches after an inactive period ofthe locus correleus. For these types of disorders, the prophylactictreatment is optimal during the inactive periods such that the amountsof inhibitory neurotransmitters in the brain can remain at a higherenough level to mitigate or abort an acute attack of the disorder.

In these embodiments, the prophylactic treatment may comprise multipledoses/day timed for periods of inactivity of the locus correleus. In oneembodiment, a treatment according to the present invention comprises oneor more doses administered 2-3 times per day or 2-3 “treatment sessions”per day. The treatment sessions preferably occur during the lateafternoon or late evening, in the middle of the night and again in themorning when the patient wakes up. In an exemplary embodiment, eachtreatment session comprises 1-4 doses, preferably 2-3 doses, with eachdose lasting for about 90 seconds to about three minutes.

For other disorders, the intervals between treatment sessions may be themost important as applicant has determined that stimulation of the vagusnerve can have a prolonged effect on the inhibitor neurotransmitterslevels in the brain, e.g., at least one hour, up to 3 hours andsometimes up to 8 hours. In one embodiment, a treatment according to thepresent invention comprises one or more doses (i.e., treatment sessions)administered at intervals during a 24-hour period. In a preferredembodiment, there are 1-5 such treatment sessions, preferably 2-4treatment sessions. Each treatment session preferably comprises 1-3doses, each lasting between about 60 seconds to about three minutes,preferably about 90 seconds to about 150 seconds, more preferably about2 minutes.

For an acute treatment, such as treatment of headache symptoms, thetherapy according to the present invention may comprise one or moreembodiments: (1) 1 dose at the onset of symptoms; (2) 1 dose at theonset of symptoms, followed by another dose at 5-15 min; or (3) 1 doseevery 15 minutes to 1 hour at the onset of symptoms until the acuteattack has been mitigated or aborted. In these embodiments, each dosepreferably last between about 60 seconds to about three minutes,preferably about 90 seconds to about 150 seconds, more preferably about2 minutes.

For long term treatment of an acute insult such as one that occurs withstroke, Alzheimer's, dementia or PCS, the therapy may consist of: (1) 3treatments/day; (2) 2 treatments, either consecutively or separated by 5min, 3×/day; (3) 3 treatments, either consecutively or separated by 5min, 2×/day; (4) 2 or 3 treatments, either consecutively or separated by5 min, up to 10×/day; or (5) 1, 2 or 3 treatments, either consecutivelyor separated by 5 min, every 15, 30, 60 or 120 min.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of strokes or concussionsthat occur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The prophylactic treatments may be most effective when the patient is ina prodromal, high-risk bistable state. In that state, the patient issimultaneously able to remain normal or exhibit symptoms, and theselection between normal and symptomatic states depends on theamplification of fluctuations by physiological feedback networks. Forexample, a thrombus may exist in either a gel or fluid phase, with thefeedback amplification of fluctuations driving the change of phaseand/or the volume of the gel phase. Thus, a thrombus may form or not,depending on the nonlinear dynamics exhibited by the network of enzymesinvolved in clot formation, as influenced by blood flow and inflammationthat may be modulated by vagus nerve stimulation [PANTELEEV M A,Balandina A N, Lipets E N, Ovanesov M V, Ataullakhanov F I.Task-oriented modular decomposition of biological networks: triggermechanism in blood coagulation. Biophys J 98(9,2010):1751-1761; Alexey MSHIBEKO, Ekaterina S Lobanova, Mikhail A Panteleev and Fazoil IAtaullakhanov. Blood flow controls coagulation onset via the positivefeedback of factor VII activation by factor Xa. BMC Syst Biol 2010;4(2010):5, pp. 1-12]. Consequently, the mechanisms of vagus nervestimulation treatment during prophylaxis for a stroke are generallydifferent than what occurs during an acute treatment, when thestimulation inhibits excitatory neurotransmission that follows the onsetof ischemia that is already caused by the thrombus. Nevertheless, theprophylactic treatment may also inhibit excitatory neurotransmission soas to limit the excitation that would eventually occur upon formation ofa thrombus, and the acute treatment may prevent the formation of anotherthrombus.

The circuits involved in such inhibition are illustrated in FIG. 1A.Excitatory nerves within the dorsal vagal complex generally useglutamate as their neurotransmitter. To inhibit neurotransmission withinthe dorsal vagal complex, the present invention makes use of thebidirectional connections that the nucleus of the solitary tract (NTS)has with structures that produce inhibitory neurotransmitters, or itmakes use of connections that the NTS has with the hypothalamus, whichin turn projects to structures that produce inhibitoryneurotransmitters. The inhibition is produced as the result of thestimulation waveforms that are described below. Thus, acting inopposition to glutamate-mediated activation by the NTS of the areapostrema and dorsal motor nucleus are: GABA, and/or serotonin, and/ornorepinephrine from the periaqueductal gray, raphe nuclei, and locuscoeruleus, respectively. FIG. 1A shows how those excitatory andinhibitory influences combine to modulate the output of the dorsal motornucleus. Similar influences combine within the NTS itself, and thecombined inhibitory influences on the NTS and dorsal motor nucleusproduce a general inhibitory effect.

The activation of inhibitory circuits in the periaqueductal gray, raphenuclei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1A [PUDOVKINA O L, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol 7(2002);445(1-2):37-42.; REICHLING D B, Basbaum A I. Collateralization ofperiaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in thefunction of the nucleus raphe magnus and in the interaction of thisnucleus with the periaqueductal gray. Brain Res 252(2,1982):299-307].The periaqueductal gray, raphe nuclei, and locus coeruleus also projectto many other sites within the brain, including those that would beexcited during ischemia. Therefore, in this aspect of the invention,vagus nerve stimulation during acute stroke or transient ischemic attackhas a general neuroprotective, inhibitory effect via its activation ofthe periaqueductal gray, raphe nuclei, and locus coeruleus.

In particular, the vagus nerve stimulation may be neuroprotective to apart of the brain known as the insula (also known as the insularycortex, insular cortex, or insular lobe) and its connections with theanterior cingulate cortex (ACC). Neural circuits leading from the vagusnerve to the insula and ACC are shown in FIG. 1A. Protection of theinsula is particularly important for stroke patients, because damage tothe insula is known to cause symptoms that are typical in strokepatients, involving motor control, hand and eye motor movement, motorlearning, swallowing, speech articulation, the capacity for long andcomplex spoken sentences, sensation, and autonomic functions [ANDERSON TJ, Jenkins I H, Brooks D J, Hawken M B, Frackowiak R S, Kennard C.Cortical control of saccades and fixation in man. A PET study. Brain117(5,1994):1073-1084; FINK G R, Frackowiak R S, Pietrzyk U, PassinghamR E (April 1997). Multiple nonprimary motor areas in the human cortex.J. Neurophysiol 77 (4,1997): 2164-2174; SOROS P, Inamoto Y, Martin R E.Functional brain imaging of swallowing: an activation likelihoodestimation meta-analysis. Hum Brain Mapp 30(8,2009):2426-2439; DRONKERSN F. A new brain region for coordinating speech articulation. Nature 384(6605,1996): 159-161; ACKERMANN H, Riecker A. The contribution of theinsula to motor aspects of speech production: a review and a hypothesis.Brain Lang 89 (2,2004): 320-328; BOROVSKY A, Saygin A P, Bates E,Dronkers N. Lesion correlates of conversational speech productiondeficits. Neuropsychologia 45 (11,2007): 2525-2533; OPPENHEIMER S M,Kedem G, Martin W M. Left-insular cortex lesions perturb cardiacautonomic tone in humans. Clin Auton Res; 6(3,1996):131-140; CRITCHLEY HD. Neural mechanisms of autonomic, affective, and cognitive integration.J. Comp. Neurol. 493 (1,2005): 154-166].

Devices of the invention that are used to stimulate a vagus nerve willnow be described. An embodiment of the present invention is shown inFIG. 1C, which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either a magnetic stimulator or theelectrode-based stimulator 302, allowing the user to change parametersettings depending on whether magnetic coils or the electrodes 340 areattached.

Although a pair of electrodes 340 is shown in FIG. 1C, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 1Crepresent all electrodes of the device collectively.

The item labeled in FIG. 1C as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Theconducting medium in which the electrode 340 is embedded need notcompletely surround an electrode. The volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, anelectrically conducting or permeable membrane, or a metal piece. In thatcase, electrical coupling of the stimulator to the patient is ohmic. Asshown, the interface may be deformable such that it is form fitting whenapplied to the surface of the body. Thus, the sinuousness or curvatureshown at the outer surface of the interface 351 corresponds also tosinuousness or curvature on the surface of the body, against which theinterface 351 is applied, so as to make the interface and body surfacecontiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's electrodes (or magnetic coils). Thesignals are selected to be suitable for amelioration of a particularmedical condition, when the signals are applied non-invasively to atarget nerve or tissue via the electrodes 340. It is noted that nervestimulating/modulating device 302 may be referred to by its function asa pulse generator. Patent application publications US2005/0075701 andUS2005/0075702, both to SHAFER, contain descriptions of pulse generatorsthat may be applicable to the present invention. By way of example, apulse generator is also commercially available, such as Agilent 33522AFunction/Arbitrary Waveform Generator, Agilent Technologies, Inc., 5301Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from a keyboard, computer mouse, and touchscreen, aswell as any externally supplied physiological signals (see FIG. 11),analog-to-digital converters for digitizing externally supplied analogsignals (see FIG. 11), communication devices for the transmission andreceipt of data to and from external devices such as printers and modemsthat comprise part of the system, hardware for generating the display ofinformation on monitors or display screens that comprise part of thesystem, and busses to interconnect the above-mentioned components. Thus,the user may operate the system by typing or otherwise providinginstructions for the control unit 330 at a device such as a keyboard ortouch-screen and view the results on a device such as the system'scomputer monitor or display screen, or direct the results to a printer,modem, and/or storage disk. Control of the system may be based uponfeedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob,or their touchscreen equivalent. In a section below, an embodiment isalso described wherein the stimulator housing has a simple structure,but other components of the control unit 330 are distributed into otherdevices (see FIG. 7).

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes, as well as the spatial distribution ofthe electric field that is produced by the electrodes. The rise time andpeak energy are governed by the electrical characteristics of thestimulator and electrodes, as well as by the anatomy of the region ofcurrent flow within the patient. In one embodiment of the invention,pulse parameters are set in such as way as to account for the detailedanatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,Robert Szmurto, Przemystaw Ptonecki, Jacek Starzynski, StanislawWincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, IOS Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2A illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe electrodes (or magnetic coils). As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the electrodes 340 that deliver the stimulating, blocking and/ormodulating impulse 410 to the nerve. Nerve stimulating/modulating device302 may be externally powered and/or recharged or may have its own powersource 320. The parameters of the modulation signal 400, such as thefrequency, amplitude, duty cycle, pulse width, pulse shape, etc., arepreferably programmable. An external communication device may modify thepulse generator programming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes,the device disclosed in patent publication No. US2005/0216062 may beemployed. That patent publication discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated, as well as the outputsof various sensors which sense prevailing conditions prevailing in thissubstance, whereby the user of the system can manually adjust thesignal, or have it automatically adjusted by feedback, to provide anelectrical stimulation signal of whatever type the user wishes, who canthen observe the effect of this signal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 100 Hz, preferably between about 15-50 Hz and morepreferably between about 15-35 Hz. In an exemplary embodiment, thefrequency is 25 Hz. The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 1microseconds to about 1000 microseconds, preferably about 100-400microseconds and more preferably about 200-400 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to 600 V/m, preferablyless than 100 V/m, and even more preferably less than 30 V/m. Thegradient of the electric field may be greater than 2 V/m/mm. Moregenerally, the stimulation device produces an electric field in thevicinity of the nerve that is sufficient to cause the nerve todepolarize and reach a threshold for action potential propagation, whichis approximately 8 V/m at 1000 Hz. The modulation signal may have a peakvoltage amplitude selected to influence the therapeutic result, such asabout 0.2 volts or greater, such as about 0.2 volts to about 40 volts,preferably between about 1-20 volts and more preferably between about2-12 volts.

An objective of some of the disclosed stimulators is to provide bothnerve fiber selectivity and spatial selectivity. Spatial selectivity maybe achieved in part through the design of the electrode (or magneticcoil) configuration, and nerve fiber selectivity may be achieved in partthrough the design of the stimulus waveform, but designs for the twotypes of selectivity are intertwined. This is because, for example, awaveform may selectively stimulate only one of two nerves whether theylie close to one another or not, obviating the need to focus thestimulating signal onto only one of the nerves [GRILL W and Mortimer JT. Stimulus waveforms for selective neural stimulation. IEEE Eng. Med.Biol. 14 (1995): 375-385]. These methods complement others that are usedto achieve selective nerve stimulation, such as the use of localanesthetic, application of pressure, inducement of ischemia, cooling,use of ultrasound, graded increases in stimulus intensity, exploitingthe absolute refractory period of axons, and the application of stimulusblocks [John E. SWETT and Charles M. Bourassa. Electrical stimulation ofperipheral nerve. In: Electrical Stimulation Research Techniques,Michael M. Patterson and Raymond P. Kesner, eds. Academic Press. (NewYork, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inpatent number U.S. Pat. No. 6,234,953, entitled Electrotherapy deviceusing low frequency magnetic pulses, to THOMAS et al. and applicationnumber US20090299435, entitled Systems and methods for enhancing oraffecting neural stimulation efficiency and/or efficacy, to GLINER etal. One may also vary stimulation parameters iteratively, in search ofan optimal setting [U.S. Pat. No. 7,869,885, entitled Thresholdoptimization for tissue stimulation therapy, to BEGNAUD et al]. However,some stimulation waveforms, such as those described herein, arediscovered by trial and error, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulationof Peripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2B and 2C. As seen there, individual sinusoidal pulses have aperiod of τ, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period τ may be between about 50-1000microseconds (equivalent to about 1-20 KHz), preferably between about100-400 microseconds (equivalent to about 2.5-10 KHz), more preferablyabout 133-400 microseconds (equivalent to about 2.5-7.5 KHZ) and evenmore preferably about 200 microseconds (equivalent to about 5 KHz); thenumber of pulses per burst may be N=1-20, preferably about 2-10 and morepreferably about 5; and the whole pattern of burst followed by silentinter-burst period may have a period T comparable to about 10-100 Hz,preferably about 15-50 Hz, more preferably about 25-35 Hz and even morepreferably about 25 Hz (a much smaller value of T is shown in FIG. 2E tomake the bursts discernable). When these exemplary values are used for Tand τ, the waveform contains significant Fourier components at higherfrequencies (1/200 microseconds=5000/sec), as compared with thosecontained in transcutaneous nerve stimulation waveforms, as currentlypracticed.

The above waveform is essentially a 1-20 KHz signal that includes burstsof pulses with each burst having a frequency of about 10-100 Hz and eachpulse having a frequency of about 1-20 KHz. Another way of thinkingabout the waveform is that it is a 1-20 KHz waveform that repeats itselfat a frequency of about 10-100 Hz. Applicant is unaware of such awaveform having been used with vagus nerve stimulation, but a similarwaveform has been used to stimulate muscle as a means of increasingmuscle strength in elite athletes. However, for the muscle strengtheningapplication, the currents used (200 mA) may be very painful and twoorders of magnitude larger than what are disclosed herein. Furthermore,the signal used for muscle strengthening may be other than sinusoidal(e.g., triangular), and the parameters τ, N, and T may also bedissimilar from the values exemplified above [A. DELITTO, M. Brown, M.J. Strube, S. J. Rose, and R. C. Lehman. Electrical stimulation of thequadriceps femoris in an elite weight lifter: a single subjectexperiment. Int J Sports Med 10(1989):187-191; Alex R WARD, NataliyaShkuratova. Russian Electrical Stimulation: The Early Experiments.Physical Therapy 82 (10,2002): 1019-1030; Yocheved LAUFER and MichalElboim. Effect of Burst Frequency and Duration of Kilohertz-FrequencyAlternating Currents and of Low-Frequency Pulsed Currents on Strength ofContraction, Muscle Fatigue, and Perceived Discomfort. Physical Therapy88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89(2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2,2009): 170-181; U.S.Pat. No. 4,177,819, entitled Muscle stimulating apparatus, to KOFSKY etal]. Burst stimulation has also been disclosed in connection withimplantable pulse generators, but wherein the bursting is characteristicof the neuronal firing pattern itself [U.S. Pat. No. 7,734,340 to D ERIDDER, entitled Stimulation design for neuromodulation; applicationUS20110184486 to D E RIDDER, entitled Combination of tonic and burststimulations to treat neurological disorders]. By way of example, theelectric field shown in FIGS. 2B and 2C may have an E_(max) value of 17V/m, which is sufficient to stimulate the nerve but is significantlylower than the threshold needed to stimulate surrounding muscle.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 11). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

The electrodes of the invention are applied to the surface of the neck,or to some other surface of the body, and are used to deliver electricalenergy non-invasively to a nerve. Embodiments of the present inventionmay differ with regard to the number of electrodes that are used, thedistance between electrodes, and whether disk or ring electrodes areused. In preferred embodiments of the method, one selects the electrodeconfiguration for individual patients, in such a way as to optimallyfocus electric fields and currents onto the selected nerve, withoutgenerating excessive currents on the surface of the skin. This tradeoffbetween focality and surface currents is described by DATTA et al.[Abhishek DATTA, Maged Elwassif, Fortunato Battaglia and Marom Bikson.Transcranial current stimulation focality using disc and ring electrodeconfigurations: FEM analysis. J. Neural Eng. 5 (2008): 163-174].Although DATTA et al. are addressing the selection of electrodeconfiguration specifically for transcranial current stimulation, theprinciples that they describe are applicable to peripheral nerves aswell [RATTAY F. Analysis of models for extracellular fiber stimulation.IEEE Trans. Biomed. Eng. 36 (1989): 676-682].

A preferred embodiment of an electrode-based stimulator is shown in FIG.3. As shown, the stimulator comprises a smartphone (31) with its backcover removed and joined to a housing (32) that comprises a pair ofelectrode surfaces (33) along with circuitry (not shown) to control andpower the electrodes and interconnect with the smartphone. The electrodesurface (33) in FIG. 3 corresponds to item 351 in FIG. 1. FIG. 3A showsthe side of the smartphone (31) with a touch-screen. FIG. 3B shows thehousing of the stimulator (32) joined to the back of the smartphone.Portions of the housing lie flush with the back of the smartphone, withwindows to accommodate smartphone components that are found on theoriginal back of the smartphone. Such components may also be used withthe stimulator, e.g., the smartphone's rear camera (34), flash (35) andspeaker (36). Other original components of the smartphone may also beused, such as the audio headset jack socket (37) and multi-purpose jack(38). Note that the original components of the smartphone shown in FIG.3 correspond to a Samsung Galaxy smartphone, and their locations may bedifferent for embodiments that use different smartphone models.

FIG. 3C shows that several portions of the housing (32) protrude towardsthe back. The two electrode surfaces (33) protrude so that they may beapplied to the skin of the patient. The stimulator may be held in placeby straps or frames or collars, or the stimulator may be held againstthe patient's body by hand. Other embodiments of the invention maycomprise a single such electrode surface or more than two electrodesurfaces.

A dome (39) also protrudes from the housing, so as to allow the deviceto lie more or less flat on a table when supported also by the electrodesurfaces. The dome also accommodates a relatively tall component thatmay lie underneath it, such as a battery. Alternatively, the stimulationdevice may be powered by the smartphone's battery. If the battery underthe dome is rechargeable, the dome may contain a socket (41) throughwhich the battery is recharged using a jack that is inserted into it,which is, for example, attached to a power cable from a base station(described below). The belly (40) of the housing protrudes to a lesserextent than the electrodes and dome. The belly accommodates a printedcircuit board that contains electronic components within the housing(not shown), as described below.

Generally, the stimulator is designed to situate the electrodes of thestimulator (340 in FIG. 1) remotely from the surface of the skin withina chamber, with conducting material (350 in FIG. 1) placed in a chamberbetween the electrode and the exterior component of the stimulator headthat contacts the skin (351 in FIG. 1). One of the novelties of thisdesign is that the stimulator, along with a correspondingly suitablestimulation waveform (see FIG. 2), shapes the electric field, producinga selective physiological response by stimulating that nerve, butavoiding substantial stimulation of nerves and tissue other than thetarget nerve, particularly avoiding the stimulation of nerves thatproduce pain. The shaping of the electric field is described in terms ofthe corresponding field equations in co-pending, commonly assignedapplication US20110230938 (application Ser. No. 13/075,746), entitledDevices and methods for non-invasive electrical stimulation and theiruse for vagal nerve stimulation on the neck of a patient, to SIMON etal., which is hereby incorporated by reference.

In certain embodiments, the disc interface 351 actually functions as theelectrode and the screw 340 is simply the output connection to thesignal generator electronics. In this embodiment, electricallyconductive fluid or gel is positioned between the signal generator andthe interface or electrode 351. In this embodiment, the conductive fluidfilters out or eliminates high frequency components from the signal tosmooth out the signal before it reaches the electrode(s) 351. When thesignal is generated, power switching and electrical noise typically addunwanted high frequency spikes back into the signal. In addition, thepulsing of the sinusoidal bursts may induce high frequency components inthe signal. By filtering the signal just before it reaches theelectrodes 351 with the conductive fluid, a smoother, cleaner signal isapplied to the patient, thereby reducing the pain and discomfort felt bythe patient and allowing a higher amplitude to be applied to thepatient. This allows a sufficiently strong signal to be applied to reacha deeper nerve, such as the vagus nerve, without causing too much painand discomfort to the patient at the surface of their skin.

In other embodiments, a low-pass filter may be used instead of theelectrically conductive fluid to filter out the undesirable highfrequency components of the signal. The low-pass filter may comprise adigital or active filter or simply two series resistors and a parallelcapacitor placed between the signal generator and theelectrode/interface.

The electrode surface (33) was shown in FIG. 3C as being roughlyhemispherical so that as the electrode surface is pressed into thepatient's skin, the surface area of skin contact would increase.However, in other designs of the electrode surface (corresponding to 351in FIG. 1), the electrode surface may be flat. Such an alternate designis shown in FIG. 4. As shown in FIG. 4A, the electrode surface (351)comprises a metal (e.g., stainless steel) disc that fits into the top ofa non-conducting (e.g., plastic) chamber (345). At the other end of thechamber, a threaded port accepts a metal screw that serves as the actualelectrode (340). A wire will be attached to the screw, connecting it toimpulse generating circuitry. The assembled components are shown in FIG.4B, which also shows the location of an electrically conducting material(350) within the chamber, such as an electrolyte solution or gel, thatallows the electrode (340) to conduct current to the external electrodesurface (351).

In one embodiment, the signal waveform (FIG. 2) that is to be applied toelectrodes of the stimulator is initially generated in a component ofthe impulse generator (310 in FIG. 1) that is exterior to, and remotefrom, the mobile phone housing. The mobile phone preferably includes asoftware application that can be downloaded into the phone to receive,from the external control component, a wirelessly transmitted waveform,or to receive a waveform that is transmitted by cable, e.g., via themulti-purpose jack 38 in FIG. 3. If the waveforms are transmitted incompressed form, they are preferably compressed in a lossless manner,e.g., making use of FLAG (Free Lossless Audio Codec). Alternatively, thedownloaded software application may itself be coded to generate aparticular waveform that is to be applied to the electrodes (340 in FIG.1C) and subsequently conveyed to the external interface of the electrodeassembly (351 in FIG. 1C and 33 in FIG. 3). In yet another embodiment,the software application is not downloaded from outside the device, butis instead available internally, for example, within read-only-memorythat is present within the housing of the stimulator (32 in FIGS. 3B and3C).

In one embodiment, the waveform is first conveyed by the softwareapplication to contacts within the phone's speaker output or theearphone jack socket (37 in FIG. 3B), as though the waveform signal werea generic audio waveform. That pseudo-audio waveform will generally be astereo waveform, representing signals that are to be applied to the“left” and “right” electrodes. The waveform will then be conveyed to thehousing of the stimulator (32 in FIGS. 3B and 3C), as follows. Thehousing of the stimulator may have an attached dangling audio jack thatis plugged into the speaker output or the earphone jack socket 37whenever electrical stimulation is to be performed, or the electricalconnection between the contacts of the speaker output or the earphonejack socket and the housing of the stimulator may be hard-wired. Ineither case, electrical circuits on a printed circuit board locatedunder the belly of the housing (40 in FIG. 3C) of the stimulator maythen shape, filter, and/or amplify the pseudo-audio signal that isreceived via the speaker output or earphone jack socket. A poweramplifier within the housing of the stimulator may then drive the signalonto the electrodes, in a fashion that is analogous to the use of anaudio power amplifier to drive loudspeakers. Alternatively, the signalprocessing and amplification may be implemented in a separate devicethat can be plugged into sockets on the phone and/or housing of thestimulator (32 in FIGS. 3B and 3C), to couple the software applicationand the electrodes.

In addition to passing the stimulation waveform from the smartphone tothe stimulator housing as described above, the smartphone may also passcontrol signals to the stimulator housing. Thus, the stimulationwaveform may generally be regarded as a type of analog, pseudo-audiosignal, but if the signal contains a signature series of pulsessignifying that a digital control signal is about to be sent, logiccircuitry in the stimulator housing may then be set to decode the seriesof digital pulses that follows the signature series of pulses, analogousto the operation of a modem.

Many of the steps that direct the waveform to the electrodes, includingsteps that may be controlled by the user via the touchscreen (31 in FIG.3A), are implemented in the above-mentioned software application. By wayof example, the software application may be written for a phone thatuses the Android operating system. Such applications are typicallydeveloped in the Java programming language using the Android SoftwareDevelopment Kit (SDK), in an integrated development environment (IDE),such as Eclipse [Mike WOLFSON. Android Developer Tools Essentials.Sebastopol, Calif.: O'Reilly Media Inc., 2013; Ronan SCHWARZ, PhilDuston, James Steele, and Nelson To. The Android Developer's Cookbook.Building Applications with the Android SDK, Second Edition. Upper SaddleRiver, N.J.: Addison-Wesley, 2013; Shane CONDER and Lauren Darcey.Android Wireless Application Development, Second Edition. Upper SaddleRiver, N.J.: Addison-Wesley, 2011; Jerome F. DIMARZIO. Android—AProgrammer's Guide. New York: McGraw-Hill. 2008. pp. 1-319]. Applicationprogramming interfaces (APIs) that are particularly relevant to theaudio features of such an Android software application (e.g.,MediaPlayer APIs) are described by: Android Open Source Project of theOpen Handset Alliance. Media Playback, at web domaindeveloper.android.com with subdomain /guide/topics/media/, Jul. 18,2014. Those APIs are also particularly relevant to the invention's useof the smartphone camera capabilities, as described below. Additionalcomponents of the software application are available from devicemanufacturers [Samsung Mobile SDK, at web domain developer.samsung.comwith subdomain /samsung-mobile-sdk, Jul. 18, 2014].

In certain embodiments, the stimulator and/or smartphone will include auser control, such as a switch or button, that disables/enables thestimulator. Preferably, the switch will automatically disable allsmartphone functions when the stimulator is enabled (and vice versa).This ensures that the medical device functionality of the smartphone iscompletely segregated from the rest of the phone's functionality. Inpreferred embodiments, the switch will be password-controlled such thatonly the patient/owner of the stimulator/phone will be able to enablethe stimulator functionality. In one such embodiment, the switch will becontrolled by a biometric scan (e.g., fingerprint, optical scan or thelike) such that the stimulator functionality can only be used by thepatient. This ensures that only the patient will be able to use theprescribed therapy in the event the phone is lost or stolen.

The stimulator and/or phone will also include software that allows thepatient to order more therapy doses over the internet (discussed in moredetail below in connection with the docking station). The purchase ofsuch therapy doses will require physician authorization through aprescription or the like. To that end, the software will preferablyinclude an authorization code that should be entered in order for thepatient to download authorization for more therapies. Without suchauthorization, the stimulator will be disabled and will not delivertherapy.

Although the device shown in FIG. 3 is an adapted commercially availablesmartphone, it is understood that in some embodiments, the housing ofthe stimulator may also be joined to and/or powered by a wireless devicethat is not a phone (e.g., Wi-Fi enabled device). Alternatively, thestimulator may be coupled to a phone or other Wi-Fi enabled devicethrough a wireless connection for exchanging data at short distances,such as Bluetooth or the like. In this embodiment, the stimulatorhousing is not attached to the smartphone and, therefore, may comprise avariety of other shapes and sizes that are convenient for the patient tocarry in his or her purse, wallet or pocket.

In other embodiments, the stimulator housing may be designed as part ofa protective or decorative case for the phone that can be attached tothe phone, similar to standard phone cases. In one such embodiment, thestimulator/case may also include additional battery life for the phoneand may include an electrical connection to the phone's battery torecharge the battery (e.g., part of a Mophie® or the like). Thiselectrical connection may also be used to couple the smartphone to thestimulator.

Reproducibility of the effects of electrical stimulation of a nerve,such as a vagus nerve, depends in part on one's ability to position theelectrode surfaces to an optimal location on the patient's skin duringsuccessive stimulation sessions. The present invention includes methodsfor repositioning the stimulation device during subsequent sessions. Themethods that are disclosed below involve initially determining anoptimal position for the stimulator by imaging the nerve withultrasound, then marking that position on the patient's skin with spotsof dyes (“tattoos”), and eventually repositioning the stimulation devicein conjunction with imaging the spots of dyes with the rear camera ofthe smartphone.

The preferred ultrasound transducer/probe used to image the vagus nerve(or other stimulated nerve) is a “hockey stick” style of probe,so-called because of its shape, which is commercially available frommost ultrasound machine manufacturers. As an example, the Hitachi AlokaUST-536 19 mm Hockey Stick style Transducer for superficial viewing hasa frequency range of 6-13 MHz, a scan angle of 90 degrees, and a probesurface area of approximately 19 mm×4 mm (Hitachi Aloka Medical America,10 Fairfield Boulevard, Wallingford Conn. 06492). The transducerconnects to the ultrasound machine that displays the anatomicalstructures that lie under the transducer.

The neck skin location for electrically stimulating the vagus nerve isdetermined preliminarily by positioning an ultrasound probe at thelocation where the center of each smartphone electrode will be placed(33 in FIG. 3), such that the vagus nerve appears in the center of theultrasound image [KNAPPERTZ V A, Tegeler C H, Hardin S J, McKinney W M.Vagus nerve imaging with ultrasound: anatomic and in vivo validation.Otolaryngol Head Neck Surg 118(1,1998):82-5]. Once that location hasbeen found for an electrode, temporary spots are marked on the patient'sneck with ink to preserve knowledge of the location and orientation ofthe ultrasound probe, through stencil holes that are attached on bothsides of the shorter dimension of the ultrasound probe. When thepreferred ultrasound location on the skin for each electrode has beenascertained, the interpolated optimal location under the center of therear camera is then marked (tattooed) on the patient's skin with one ofthe more permanent fluorescent dyes that are described below. Theinterpolation may be performed using a long, rectangular stencil withseveral holes, wherein holes near the ends of the stencil are alignedwith the temporary spots that had been marked for the electrodelocations, and wherein a central hole of the stencil is used to applythe permanent fluorescent dye to a location that will lie under thesmartphone camera. Ordinarily two or more adjacent fluorescent dyelocations are marked, such that if the stencil is subsequently alignedcentrally over the fluorescent spots on the skin, the end holes of thestencil would also align with the temporary spot locations that had beenmarked to record the ultrasound probe location matching electrodelocations.

It is understood that any non-toxic dye may be used to permanently marka location on the patient's skin. However, the preferred type ofpermanent dye is a fluorophore that is only visible or detectable as aspot on the patient's neck when one shines non-visible light upon it,e.g., ultraviolet light (“blacklight”) or infrared light. This isbecause the patient is thereby spared the embarrassment of explainingwhy there would otherwise be a visible spot mark on his or her neck, andalso because such a dye is suitable for showing where to place thestimulator irrespective of whether the patient is dark-skinned orlight-skinned. Another method, which is to attempt to match the color ofthe dye to the patient's flesh color, would be generally impractical.Marking with a fluorescent dye (e.g., from ordinary highlighting pens)has been performed previously by surgeons and radiologists to outlinewhere a procedure is to be performed. However, the marking in thepresent invention is different in that it is intended to be usedrepeatedly by a patient alone for device positioning at small discretespots [DAVID, J. E., Castle, S. K. B., and Mossi, K. M. Localizationtattoos: an alternative method using fluorescent inks. RadiationTherapist 15(2006):1-5; WATANABE M, Tsunoda A, Narita K, Kusano M, MiwaM. Colonic tattooing using fluorescence imaging with light-emittingdiode-activated indocyanine green: a feasibility study. Surg Today39(3,2009):214-218].

Once the position-indicating fluorescent spots have been applied on thepatient's skin as described above, they may fade and eventuallydisappear as the stained outer surface of the patient's skin exfoliates.The exfoliation will occur naturally as the patient washes his or herneck and may be accelerated by mechanical (e.g., abrasive) or chemicalmethods that are routinely used by cosmetologists. Before the spotdisappears, the patient or a family member may reapply thedye/fluorophor to the same spot while observing it with ultraviolet orinfrared light (as the case may be), by masking the skin outside thespot and then applying new dye solution directly with a cotton swab.Viewing of the fluorescence that is excited by ultraviolet light can bedone with the naked eye because it comprises blue light, and viewing offluorescence that is excited by infrared light can be done with aconventional digital camera after removing the camera's IR-blockingfilter. For some cameras, removal of an IR-blocking filter may not benecessary (e.g., those that can perform retinal biometric scans). Someof the infrared fluorescent dyes may also be faintly visible to thenaked eye even under room light, depending on their concentration (e.g.,indocyanine green).

Alternatively, a semi-permanent or permanent tattooing method of markingor re-marking the fluorescent spots may be used by a licensedprofessional tattooer, by injecting the dye/fluorophor into an outerskin layer or deeper into the skin [Maria Luisa Perez-COTAPOS, ChristaDe Cuyper, and Laura Cossio. Tattooing and scarring: techniques andcomplications. In: Christa de Cuyper and Maria Luisa Cotapos (Eds.).Dermatologic Complications with Body Art: Tattoos, Piercings andPermanent Make-Up. Berlin and London: Springer, 2009, pp. 31-32].

Many dyes can be used for the ultraviolet marking, but the mostconvenient ones for skin-surface marking are those that are commerciallyavailable to hand-stamp attendees of events. For tattooing applications,ultraviolet-absorbing injectable fluorophores are commercially availablethat are encapsulated within microspheres [Technical sheet for Opticz UVBlacklight Reactive Blue Invisible Ink. 2013. Blacklight.com, 26735 WCommerce Dr Ste 705, Volo, Ill. 60073-9658; Richard P. HAUGLAND.Fluorophores excited with UV light. Section 1.7 In: The Molecular ProbesHandbook: A Guide to Fluorescent Probes and Labeling Technologies, 11thEdition, 2010. Molecular Probes/Life Technologies. 4849 Pitchford Ave.,Eugene, Oreg. 97402. pp. 66-73; Technical sheet for BIOMATRIX System.2013. NEWWEST Technologies, Santa Rosa Calif. 95407-0286].

Many dyes can also be used for the infrared marking, their majoradvantage being that auto-fluorescence from human skin or tissuegenerally does not interfere with detection of their fluorescence. Infact, the infrared fluorophores may be imaged up to about twocentimeters under the skin. Examples of such dyes are indocyanine greenand Alexa Fluor 790. Quantum dots may also be used to generate infraredfluorescence, advantages of which are that they are very stable and verybrightly fluorescent. They may also be encapsulated in microspheres forpurposes of tattooing. Quantum dots may also be electroluminescent, suchthat the electric field and currents produced by the stimulator mightalone induce the emission of infrared light from the quantum dots[Richard P. HAUGLAND. Alexa Fluor Dyes Spanning the Visible and InfraredSpectrum—Section 1.3; and Qdot Nanocrystals—Section 6.6. In: TheMolecular Probes Handbook: A Guide to Fluorescent Probes and LabelingTechnologies, 11th Edition, 2010. Molecular Probes/Life Technologies.4849 Pitchford Ave., Eugene, Oreg. 97402; GRAVIER J, Navarro F P, DelmasT, Mittler F, Couffin A C, Vinet F, Texier I. Lipidots: competitiveorganic alternative to quantum dots for in vivo fluorescence imaging. JBiomed Opt. 16(9,2011):096013; ROMOSER A, Ritter D, Majitha R, MeissnerK E, McShane M, Sayes C M. Mitigation of quantum dot cytotoxicity bymicroencapsulation. PLoS One. 6(7,2011):e22079:pp. 1-7; Andrew M. SMITH,Michael C. Mancini, and Shuming Nie. Second window for in vivo imaging.Nat Nanotechnol 4(11,2009): 710-711].

Once the patient is ready to apply the stimulator to the neck (as shownin FIGS. 8 and 10), he or she will place a snap-in optical attachment(50 in FIG. 5C) on the back of the smartphone, at a location on top ofthe rear camera (34 in FIG. 3B) and camera flash (35 in FIG. 3B), andbetween the electrode surfaces (33 in FIGS. 3 and 5). The purpose of theoptical attachment is to facilitate optimal positioning of theelectrodes, by forming a camera image of fluorescence from the spots ofdye that had been placed in or under the patient's skin.

Once the snap-in optical attachment is in place, apertures are formedbetween the optical attachment and the rear camera/flash, as indicatedby 34′ and 35′ in FIGS. 5A, 5B, and 5C. The optical elements shown inFIGS. 5A and 5B that are situated above the apertures are present in thesmartphone, and the optical elements situated below the apertures inthose figures are components of the snap-in optical attachment. Theoptical elements in the smartphone include a flash, which is alight-emitting diode (LED) 43 that may be programmed to provideillumination while taking a photograph (or may be even be programmed toserve as a flashlight). Without the snap-in optical attachment, lightreflected back from the LED-illuminated objects would be imaged by alens 44 that is internal to the smartphone. When the snap-in opticalattachment is in place, a macro lens (56 in FIGS. 5A, 5B, and 5C) withinthe attachment allows for the imaging of close objects, which in thisapplication will be fluorescence 55 emanating from the fluorescent spotof dye 59, on or under the patient's skin 58. As an example, the macrolens may be similar to ones sold by Carson Optical [LensMag™—modelML-415, Carson Optical, 35 Gilpin Avenue, Hauppauge, N.Y. 11788].

In order to produce fluorescence from the fluorescent dye in thepatient's skin, the dye should be illuminated with wavelengthscorresponding to peaks in its excitation spectrum. In the preferredembodiment of the invention, infrared illumination causes the dye (e.g.,indocyanine green) to fluoresce at a wavelength greater than 820 nm, andthe LED may be used to illuminate the dye at its excitation wavelengthnear 760 or 785 nm. Because the LED found in some smartphone cameras mayonly generate light predominantly in the visible range (400-700 nm), theoptical components shown in FIG. 5A are used to shift the light towardsthe preferred infrared excitation wavelengths. As light leaves the LED43 of the flash unit, it first encounters a dichroic mirror 51 thatpasses light with a wavelength less than 700 nm (visible light) andreflects light with wavelengths greater than 700 nm (infrared light).The light passing through the dichroic mirror then encounters a film ofphosphorescent material 52 that absorbs the visible light and emitsphosphorescent infrared light with a peak in the range of about 760 to785 nm [Haifeng XIANG, Jinghui Cheng, Xiaofeng Ma, Xiangge Zhou andJason Joseph Chruma. Near-infrared phosphorescence: materials andapplications. Chem. Soc. Rev. 42(2013): 6128-6185]. If thephosphorescent infrared light is emitted back towards the LED, then thedichroic mirror 51 reflects the phosphorescence back into a chamber 53,where it joins phosphorescence that is emitted in the direction awayfrom the LED. The chamber 53 is coated internally with a reflectivematerial such as silver, so that the phosphorescence may undergomultiple reflections from the silver or from the dichroic mirror 51,until it eventually emerges as light from a slit 54 that is directedtowards the spots on the patient's skin. Similarly, visible light thatpasses through the phosphorescent layer 52 without generatingphosphorescence may also undergo multiple reflections from the silvercoating until it encounters the phosphorescent layer 52 again, whichthis time may produce phosphorescence, or it may pass back through thedichroic mirror and be lost (along with first-pass visible light that isbackscattered from the phosphorescent layer), unless it is reflectedback through the dichroic mirror 51 from the surface of the LED. Some ofthe visible light that enters the chamber 53 may also emerge as lightfrom the slit 54. However, the visible light emerging from the slit doesnot have wavelengths needed to produce fluorescence 55 from the infrareddye 59 in the patient's skin 58. Furthermore, any of the visible lightthat emerges from the slit and eventually makes its way through themacro lens 56 would be blocked by a filter 57 that passes only lighthaving a wavelength greater than about 800 nm. Thus, the filter 57 willblock not only any visible light from the LED, but also the excitationinfrared wavelengths less than about 780 nm that are produced by thephosphorescent layer 52. The light that does pass through the filter 57will be mostly fluorescence from the spot of dye 59, and thatfluorescence will be imaged by the lens 44 onto the light-sensitiveelements in the smartphone's rear camera, thereby producing an image ofthe fluorescent spot.

Note that the foregoing description presumes that there is a gap betweenthe macro lens 56 and the patient's skin 58, such that the excitationwavelengths of light may pass under the macro lens to wherever theinfrared dye 59 may be located. This would generally be the case becausethe height of the electrode surfaces (33′ in FIGS. 5A and 5B) preventthe macro lens 56 from reaching the surface of the patient's skin.However, even if the macro lens 56 were pressed all the way to thesurface of the skin, a spot of fluorescent dye 59 could still be excitedby the light if it had been injected deeper than the surface of theskin. This is because infrared light may penetrate up to about 2 cmthrough the skin.

In the event that the LED 43 produces light with wavelengths that aresuitable for excitation of the fluorescent dye, then the phosphorescentlayer 52 that is shown in FIG. 5A is not necessary. For example, thiswould be the case if the LED 43 produces sufficient light withwavelengths around 760 nm to 785 nm, which would excite the infrared dyeindocyanine green. This would also be the case if one were exciting adye that is excited with light in the ultraviolet and violet range,producing blue fluorescence. In those cases, the snap-in opticalattachment shown in FIG. 5B would be more appropriate. As shown there, afilter 51′ would pass light with wavelengths only in the range thatexcites the fluorophore, and it therefore would not pass the wavelengthsof fluorescence that are emitted by the fluorophore (or otherconfounding wavelengths). The excitation illumination will then enter achamber 53′ with reflective internal surfaces, such that the excitationlight will appear as light emanating from a slit 54′, which is directedtowards the fluorophore spot 59 in or under the patient's skin 58. Thatexcitation illumination will then cause the fluorophore spot in thepatient's skin to emit fluorescent light 55, which will be collected bythe macro lens 56. Light corresponding to the excitation wavelengthswill also be collected by the macro lens 56, but a filter 57′ will blockthe excitation wavelengths of light and pass only the fluorescence. Thefluorescence will then be collected by the smartphone's lens 44 and beimaged onto the photosensitive material of the smartphone's camera,thereby producing an image of the fluorescent spot in or under thepatient's skin.

During initial testing of the stimulator on the patient, the appropriatesnap-in optical attachment will be in place (as described above), andthe smartphone's camera will be turned on, while electrical impulsesfrom the electrode surfaces 33 are applied to the patient's skin. If theelectrodes are near their optimal position on the patient's skin, thefluorescent spots that had been applied to the patient's skin shouldthen appear in an image produced by the smartphone's camera, viewable onthe screen of the smartphone (31 in FIG. 3). The electrodes may then beslightly translated, rotated, and depressed into the patient's skin,until a maximum therapeutic response is achieved. Methods for evaluatingthe response at a particular stimulator setting were disclosed in acommonly assigned, co-pending application U.S. Ser. No. 13/872,116(publication No. US20130245486), entitled DEVICES AND METHODS FORMONITORING NON-INVASIVE VAGUS NERVE STIMULATION, to SIMON et al, whichis hereby incorporated by reference. Once the maximum therapeuticposition of the electrodes has been decided, a reference image of thefluorescent spots will then be recorded at that position and saved inthe memory of the smartphone for future reference.

During subsequent sessions when the patient applies the stimulator tohis or her skin, the appropriate snap-in optical attachment will also bein place, and the smartphone's camera will be turned on, whileelectrical impulses from the electrode surfaces 33 are applied to thepatient's skin. The fluorescent spots that had been applied to thepatient's skin should then also appear in an image produced by thesmartphone's camera, viewable on the screen of the smartphone (31 inFIG. 3). By superimposing the currently viewed image of the fluorescentspots onto the previously recorded reference image of the fluorescentspots, one may then ascertain the extent to which the current position,orientation, and depth-into-the-skin of the electrode surfaces match thepreviously recorded optimal reference position. This is illustrated inFIG. 6, which shows the currently imaged fluorescent spots and thesuperimposed reference spots, as well as the rotation and translationneeded to align the former onto the latter spots. Instead ofsuperimposing images of the current and reference images of the spots,one may also subtract the two images, pixel-by-pixel, and display theabsolute value of the difference. In that case, optimal positioning ofthe electrode surfaces would occur when the reference imageapproximately nulls the current image. The sum of the pixel values inthe nulled image may then be used as an index of the extent to which thecurrent and reference images coincide. The control unit of thestimulator may also be configured to disable electrical stimulation ofthe vagus nerve unless a pre-determined cutoff in the index of alignmentof the images has been achieved. For example, use of such a fluorescentspot alignment index may be used to ensure that the patient isattempting to stimulate the vagus nerve on the intended side of theneck. It is understood, however, that the fluorescence alignment methoddescribed above may not be suitable for all patients, particularlypatients having necks that are significantly wrinkled or that containlarge amounts of fatty tissue.

In one embodiment of the present invention, significant portions of thecontrol of the vagus nerve stimulation reside in controller componentsthat are physically separate from the housing of the stimulator. In thisembodiment, separate components of the controller and stimulator housinggenerally communicate with one another wirelessly. Thus, the use ofwireless technology avoids the inconvenience and distance limitations ofinterconnecting cables. Additional reasons in the present disclosure forphysically separating many components of the controller from thestimulator housing are as follows.

First, the stimulator may be constructed with the minimum number ofcomponents needed to generate the stimulation pulses, with the remainingcomponents placed in parts of the controller that reside outside thestimulator housing, resulting in a lighter and smaller stimulatorhousing. In fact, the stimulator housing may be made so small that itcould be difficult to place, on the stimulator housing's exterior,switches and knobs that are large enough to be operated easily. Instead,for the present disclosure, the user may generally operate the deviceusing the smartphone touchscreen.

Second, the controller (330 in FIG. 1C) may be given additionalfunctions when free from the limitation of being situated within or nearthe stimulator housing. For example, one may add to the controller adata logging component that records when and how stimulation has beenapplied to the patient, for purposes of medical recordkeeping andbilling. The complete electronic medical record database for the patientmay be located far from the stimulator (e.g., somewhere on theinternet), and the billing system for the stimulation services that areprovided may also be elsewhere, so it would be useful to integrate thecontroller into that recordkeeping and billing system, using acommunication system that includes access to the internet or telephonenetworks.

Third, communication from the databases to the controller would also beuseful for purposes of metering electrical stimulation of the patient,when the stimulation is self-administered. For example, if theprescription for the patient only permits only a specified amount ofstimulation energy to be delivered during a single session of vagusnerve stimulation, followed by a wait-time before allowing the nextstimulation, the controller can query the database and then permit thestimulation only when the prescribed wait-time has passed. Similarly,the controller can query the billing system to assure that the patient'saccount is in order, and withhold the stimulation if there is a problemwith the account.

Fourth, as a corollary of the previous considerations, the controllermay be constructed to include a computer program separate from thestimulating device, in which the databases are accessed via cell phoneor internet connections.

Fifth, in some applications, it can be important that the stimulatorhousing and parts of the controller be physically separate. For example,when the patient is a child, one wants to make it impossible for thechild to control or adjust the vagus nerve stimulation. The bestarrangement in that case is for the stimulator housing to have notouchscreen elements, control switches or adjustment knobs that could beactivated by the child. Alternatively, any touchscreen elements,switches and knobs on the stimulator can be disabled, and control of thestimulation then resides only in a remote controller with a child-proofoperation, which would be maintained under the control of a parent orhealthcare provider.

Sixth, in some applications, the particular control signal that istransmitted to the stimulator by the controller will depend onphysiological and environmental signals that are themselves transmittedto and analyzed by the controller. In such applications, many of thephysiological and environmental signals may already be transmittedwirelessly, in which case it is most convenient to design an externalpart of the controller as the hub of all such wireless activity,including any wireless signals that are sent to and from the stimulatorhousing.

With these considerations in mind, an embodiment of the inventionincludes a base station that may send/receive data to/from thestimulator, and may send/receive data to/from databases and othercomponents of the system, including those that are accessible via theinternet. Typically, the base station will be a laptop computer attachedto additional components needed for it to accomplish its function. Thus,prior to any particular stimulation session, the base station may loadinto the stimulator (FIG. 3) parameters of the session, includingwaveform parameters, or the actual waveform. See FIG. 2. In oneembodiment, the base station is also used to limit the amount ofstimulation energy that may be consumed by the patient during thesession, by charging the stimulator's rechargeable battery (see 41 inFIG. 3) with only a specified amount of releasable electrical energy,which is different than setting a parameter to restrict the duration ofa stimulation session. Thus, the base station may comprise a powersupply that may be connected to the stimulator's rechargeable battery,and the base station meters the recharge. As a practical matter, thestimulator may therefore use two batteries, one for applying stimulationenergy to the electrodes (the charge of which may be limited by the basestation) and the other for performing other functions. Methods forevaluating a battery's charge or releasable energy are known in the art,for example, in patent U.S. Pat. No. 7,751,891, entitled Power supplymonitoring for an implantable device, to ARMSTRONG et al. Alternatively,control components within the stimulator housing may monitor the amountof electrode stimulation energy that has been consumed during astimulation session and stop the stimulation session when a limit hasbeen reached, irrespective of the time when the limit has been reached.

The communication connections between different components of thestimulator's controller are shown in FIG. 7, which is an expandedrepresentation of the control unit 330 in FIG. 1C. Connection betweenthe base station controller components 332 and components within thestimulator housing 331 is denoted in FIG. 7 as 334. Connection betweenthe base station controller components 332 and internet-based orsmartphone components 333 is denoted as 335. Connection between thecomponents within the stimulator housing 331 and internet-based orsmartphone components 333 is denoted as 336. For example, controlconnections between the smartphone and stimulator housing via the audiojack socket would fall under this category, as would any wirelesscommunication directly between the stimulator housing itself and adevice situated on the internet. In principle, the connections 334, 335and 336 in FIG. 7 may be either wired or wireless. Different embodimentsof the invention may lack one or more of the connections.

Although infrared or ultrasound wireless control might be used tocommunicate between components of the controller, they are not preferredbecause of line-of-sight limitations. Instead, in the presentdisclosure, the communication between devices preferably makes use ofradio communication within unlicensed ISM frequency bands (260-470 MHz,902-928 MHz, 2400-2.4835 GHz). Components of the radio frequency systemin devices in 331, 332, and 333 typically comprise a system-on-chiptransciever with an integrated microcontroller; a crystal; associatedbalun & matching circuitry, and an antenna [Dag GRINI. RF Basics, RF forNon-RF Engineers. Texas Instruments, Post Office Box 655303, Dallas,Tex. 75265, 2006].

Transceivers based on 2.4 GHz offer high data rates (greater than 1Mbps) and a smaller antenna than those operating at lower frequencies,which makes them suitable for with short-range devices. Furthermore, a2.4 GHz wireless standard (Bluetooth, Wi-Fi, and ZigBee) may be used asthe protocol for transmission between devices. Although the ZigBeewireless standard operates at 2.4 GHz in most jurisdictions worldwide,it also operates in the ISM frequencies 868 MHz in Europe, and 915 MHzin the USA and Australia. Data transmission rates vary from 20 to 250kilobits/second with that standard. Because many commercially availablehealth-related sensors may operate using ZigBee, its use may berecommended for applications in which the controller uses feedback andfeedforward methods to adjust the patient's vagus nerve stimulationbased on the sensors' values, as described below in connection with FIG.11 [ZigBee Wireless Sensor Applications for Health, Wellness andFitness. ZigBee Alliance 2400 Camino Ramon Suite 375 San Ramon, Calif.94583].

A 2.4 GHz radio has higher power consumption than radios operating atlower frequencies, due to reduced circuit efficiencies. Furthermore, the2.4 GHz spectrum is crowded and subject to significant interference frommicrowave ovens, cordless phones, 802.11b/g wireless local areanetworks, Bluetooth devices, etc. Sub-GHz radios enable lower powerconsumption and can operate for years on a single battery. Thesefactors, combined with lower system cost, make sub-GHz transceiversideal for low data rate applications that need maximum range andmulti-year operating life.

The antenna length needed for operating at different frequencies is 17.3cm at 433 MHz, 8.2 cm at 915 MHz, and 3 cm at 2.4 GHz. Therefore, unlessthe antenna is included in a neck collar that supports the device shownin FIG. 3, the antenna length may be a disadvantage for 433 MHztransmission. The 2.4 GHz band has the advantage of enabling one deviceto serve in all major markets worldwide since the 2.4 GHz band is aglobal spectrum standard. However, 433 MHz is a viable alternative to2.4 GHz for most of the world, and designs based on 868 and 915 MHzradios can serve the US and European markets with a single product.

Range is determined by the sensitivity of the transceiver and its outputpower. A primary factor affecting radio sensitivity is the data rate.Higher data rates reduce sensitivity, leading to a need for higheroutput power to achieve sufficient range. For many applications thatrequire only a low data rate, the preferred rate is 40 Kbps where thetransceiver can still use a standard off-the-shelf 20 parts per millioncrystal.

A typical signal waveform that might be transmitted wirelessly to thestimulator housing was shown in FIGS. 2B and 2C. As seen there,individual sinusoidal pulses have a period of tau, and a burst consistsof N such pulses. This is followed by a period with no signal (theinter-burst period). The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period tau may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation (a much smaller value of T is shown inFIG. 2C to make the bursts discernable). When these exemplary values areused for T and tau, the waveform contains significant Fourier componentsat higher frequencies (1/200 microseconds=5000/sec). Such a signal maybe easily transmitted using 40 Kbps radio transmission. Compression ofthe signal is also possible, by transmitting only the signal parameterstau, N, T, Emax, etc., but in that case the stimulator housing's controlelectronics would then have to construct the waveform from thetransmitted parameters, which would add to the complexity of componentsof the stimulator housing.

However, because it is contemplated that sensors attached to thestimulator housing may also be transmitting information, the datatransfer requirements may be substantially greater than what is requiredonly to transmit the signal shown in FIG. 2. Therefore, the presentinvention may make use of any frequency band, not limited to the ISMfrequency bands, as well as techniques known in the art to suppress oravoid noise and interferences in radio transmission, such as frequencyhopping and direct sequence spread spectrum.

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retropharyngeal spaceon each side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 8 illustrates use of the device 30 shown in FIG. 3 (30 in FIG.8=31+32 in FIG. 3) to stimulate the vagus nerve at that location in theneck, in which the stimulator device 30 is shown to be applied to thetarget location on the patient's neck as described above. For reference,FIG. 8 shows the locations of the following vertebrae: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77. Because the smartphone isapplied to the patient's neck, the patient will generally need a mirror29 to view and touch the phone's touchscreen. Therefore, the imagesdisplayed on the phone's screen may be reversed when the device is usedas shown in FIG. 8. Alternatively, the images displayed on the phone'sscreen may be transmitted wirelessly to a computer program in the basestation, which will display the images on the computer screen of thebase station, and the patient may interact with the smartphonewirelessly via the base station.

FIG. 9 shows the stimulator 30 applied to the neck of a child, which ispartially immobilized with a foam cervical collar 78 that is similar toones used for neck injuries and neck pain. The collar is tightened witha strap 79, and the stimulator is inserted through a hole in the collarto reach the child's neck surface. In such applications, the stimulatormay be turned on and off remotely, using a wireless controller that maybe used to adjust the stimulation parameters of the controller (e.g.,on/off, stimulation amplitude, frequency, etc.).

FIG. 10 provides a more detailed view of use of the electricalstimulator 30, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 8. The anatomy shown in FIG. 10 is across-section of half of the neck at vertebra level C6. The vagus nerve60 is identified in FIG. 10, along with the carotid sheath 61 that isidentified there in bold peripheral outline. The carotid sheath enclosesnot only the vagus nerve, but also the internal jugular vein 62 and thecommon carotid artery 63. Structures that may be identified near thesurface of the neck include the external jugular vein 64 and thesternocleidomastoid muscle 65, which protrudes when the patient turnshis or her head. Additional organs in the vicinity of the vagus nerveinclude the trachea 66, thyroid gland 67, esophagus 68, scalenusanterior muscle 69, scalenus medius muscle 70, levator scapulae muscle71, splenius colli muscle 72, semispinalis capitis muscle 73,semispinalis colli muscle 74, longus colli muscle and longus capitismuscle 75. The sixth cervical vertebra 76 is shown with bony structureindicated by hatching marks. Additional structures shown in the figureare the phrenic nerve 77, sympathetic ganglion 78, brachial plexus 79,vertebral artery and vein 80, prevertebral fascia 81, platysma muscle82, omohyoid muscle 83, anterior jugular vein 84, sternohyoid muscle 85,sternothyroid muscle 86, and skin with associated fat 87.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 8, 9, and 10, using the electrical stimulationdevices that are disclosed here. Stimulation may be performed on theleft or right vagus nerve or on both of them simultaneously oralternately. The position and angular orientation of the device areadjusted about that location until the patient perceives stimulationwhen current is passed through the stimulator electrodes. The appliedcurrent is increased gradually, first to a level wherein the patientfeels sensation from the stimulation. The power is then increased, butis set to a level that is less than one at which the patient firstindicates any discomfort. Straps, harnesses, or frames may be used tomaintain the stimulator in position. The stimulator signal may have afrequency and other parameters that are selected to produce atherapeutic result in the patient, i.e., stimulation parameters for eachpatient are adjusted on an individualized basis. Ordinarily, theamplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. As seen there, individual sinusoidal pulses have aperiod of τ, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period τ may be between about 50-1000microseconds (equivalent to about 1-20 KHz), preferably between about100-400 microseconds (equivalent to about 2.5-10 KHz), more preferablyabout 133-400 microseconds (equivalent to about 2.5-7.5 KHZ) and evenmore preferably about 200 microseconds (equivalent to about 5 KHz); thenumber of pulses per burst may be N=1-20, preferably about 2-10 and morepreferably about 5; and the whole pattern of burst followed by silentinter-burst period may have a period T comparable to about 10-100 Hz,preferably about 15-50 Hz, more preferably about 25-35 Hz and even morepreferably about 25 Hz (a much smaller value of T is shown in FIG. 2C tomake the bursts discernable). When these exemplary values are used for Tand τ, the waveform contains significant Fourier components at higherfrequencies (1/200 microseconds=5000/sec), as compared with thosecontained in transcutaneous nerve stimulation waveforms, as currentlypracticed.

When a patient is using the stimulation device to performself-stimulation therapy, e.g., at home or at a workplace, he or shewill follow the steps that are now described. It is assumed that theoptimal stimulation position has already been marked on the patient'sneck, as described above and that a reference image of the fluorescentspots has already been acquired. The previous stimulation session willordinarily have discharged the rechargeable batteries of the stimulatorhousing, and between sessions, the base station will have been used torecharged the stimulator at most only up to a minimum level. If thestimulator's batteries had charge remaining from the previousstimulation session, the base station will discharge the stimulator to aminimum level that will not support stimulation of the patient.

The patient can initiate the stimulation session using the mobile phoneor base station (e.g., laptop computer) by invoking a computer program(on the laptop computer or through an app on the mobile phone) that isdesigned to initiate use of the stimulator. The programs in thesmartphone and base station may initiate and interact with one anotherwirelessly, so in what follows, reference to the program (app) in thesmartphone may also apply to the program in the base station, becauseboth may be operating in tandem. For security reasons, the program wouldbegin with the request for a user name and a password, and that user'sdemographic information and any data from previous stimulatorexperiences would already be associated with it in the login account.The smartphone may also be used to authenticate the patient using afingerprint or voice recognition app, or other reliable authenticationmethods. If the patient's physician has not authorized furthertreatments, the base station will not charge the stimulator's batteries,and instead, the computer program will call or otherwise communicatewith the physician's computer requesting authorization. Afterauthorization by the physician is received, the computer program (on thelaptop computer or through an app on the mobile phone) may also query adatabase that is ordinarily located somewhere on the internet to verifythat the patient's account is in order. If it is not in order, theprogram may then request prepayment for one or more stimulationsessions, which would be paid by the patient using a credit card, debitcard, PayPal or the like. The computer program will also query itsinternal database or that of the base station to determine thatsufficient time has elapsed between when the stimulator was last usedand the present time, to verify that any required wait-time has elapsed.

Having received authorization to perform a nerve stimulation session,the patient interface computer program will then ask the patientquestions that are relevant to the selection of parameters that the basestation will use to make the stimulator ready for the stimulationsession. The questions that the computer program asks are dependent onthe condition for which the patient is being treated, which for presentpurposes is considered to be treatment for a migraine headache. Thatheadache may in principle be in any of the headache phases (prodrome,aura, headache pain, postdrome, and interictal period), which would beascertained through the computer program's questions. The questions maybe things like (1) is this an acute or prophylactic treatment? (2) ifacute, then how severe is your headache, how long have you had it, (3)has anything unusual or noteworthy occurred since the last stimulation?,etc. In general, the types of posed questions are ones that would beplaced in a headache diary [TASSORELLI C, Sances G, Allena M, Ghiotto N,Bendtsen L, Olesen J, Nappi G, Jensen R. The usefulness andapplicability of a basic headache diary before first consultation:results of a pilot study conducted in two centers. Cephalalgia28(10,2008):1023-1030].

Having received such preliminary information from the patient, thecomputer programs will perform instrument diagnostic tests and make thestimulator ready for the stimulation session. In general, the algorithmfor setting the stimulator parameters will have been decided by thephysician and will include the extent to which the stimulator batteriesshould be charged, which the vagus nerve should be stimulated (right orleft), and the time that the patient should wait after the stimulationsession is ended until initiation of a subsequent stimulation session.The computer will query the physician's computer to ascertain whetherthere have been any updates to the algorithm, and if not, will use theexisting algorithm. The patient will also be advised of the stimulationsession parameter values by the interface computer program, so as toknow what to expect.

Once the base station has been used to charge the stimulator's batteriesto the requisite charge, the computer program (or smartphone app) willindicate to the patient that the stimulator is ready for use. At thatpoint, the patient would attach to the smartphone the optical attachment50 shown in FIG. 5, clean the electrode surfaces, and make any otherpreliminary adjustments to the hardware. The stimulation parameters forthe session will be displayed, and any options that the patient isallowed to select may be made. Once the patient is ready to begin, he orshe will press a “start” button on the touchscreen and may begin thevagus nerve stimulation, as shown in FIG. 8.

Multiple methods may be used to test whether the patient is properlyattempting to stimulate the vagus nerve on the intended side of theneck. For example, accelerometers and gyroscopes within the smartphonemay be used to determine the position and orientation of thesmartphone's touch screen relative to the patient's expected view of thescreen, and a decision by the stimulator's computer program as to whichhand is being used to hold the stimulator may be made by measuringcapacitance on the outside of the stimulator body, which may distinguishfingers wrapped around the device versus the ball of a thumb [RaphaelWIMMER and Sebastian Boring. HandSense: discriminating different ways ofgrasping and holding a tangible user interface. Proceedings of the 3rdInternational Conference on Tangible and Embedded Interaction, pp.359-362. ACM New York, N.Y., 2009]. Pressing of the electrodes againstthe skin will result in a resistance drop across the electrodes, whichcan initiate operation of the rear camera. A fluorescent image shouldappear on the smartphone screen only if the device is applied to theside of the neck in the vicinity of the fluorescent spots that had beenapplied as a tattoo earlier. If the totality of these data indicates tothe computer program that the patient is attempting to stimulate thewrong vagus nerve or that the device is being held improperly, thestimulation will be withheld, and the stimulator may then communicatewith the patient via the interface computer program (in the mobile phoneor laptop computer) to alert the patient of that fact. The program maythen offer suggestions on how to better apply the device to the neck.

However, if the stimulator is being properly applied, and an image ofthe fluorescent spots on the patient's neck appears on the screen of thephone, the stimulator begins to stimulate according to predeterminedinitial stimulus parameters. The patient will then adjust the positionand angular orientation of the stimulator about what he or she thinks isthe correct neck position, until he or she perceives stimulation whencurrent is passed through the stimulator electrodes. An attempt is alsomade to superimpose the currently viewed fluorescence image of the neckspots with the previously acquired reference image. The applied currentis increased gradually using keys on the keyboard of the base station oron the smartphone touchscreen, first to a level wherein the patientfeels sensation from the stimulation. The stimulation amplitude is thenincreased by the patient, but is set to a level that is less than one atwhich he first senses any discomfort. By trial and error, thestimulation is then optimized by the patient, who tries to find thegreatest acceptable sensation with the lowest acceptable stimulationamplitude, with the stimulator aligned using the fluorescent spots. Ifthe stimulator is being held in place by hand, it is likely that theremay be inadvertent fluctuating movement of the stimulator, due forexample to neck movement during respiration. Such relative movementswill affect the effectiveness of the stimulation. However, they may bemonitored by accelerometers and gyroscopes within the smartphone, whichmay be transmitted as movement data from the stimulator to the patientinterface computer program (in the mobile phone or laptop computer). Therelative movements may also be monitored and measured as fluctuations inthe position of the fluorescence spots that are being imaged. Bywatching a graphical display of the relative movements shown by thepatient interface computer program, the patient may use that display inan attempt to deliberately minimize the movements. Otherwise, thepatient may attempt to adjust the amplitude of the stimulator ascompensation for movement of the stimulator away from its optimumposition. In a section that follows, it is described how the stimulatoritself may modulate the amplitude of the stimulation in order to makesuch compensations.

During the session, the patient may lift the stimulator from his neck,which will be detected as an increase in resistance between theelectrodes and a loss of the fluorescent image of the spots on thepatient's neck. When that occurs, the device will withhold power to thestimulator for reasons of safety. The patient can then reapply thestimulator to his neck to resume the session, although the interruptionof stimulation will be recognized and recorded by the computer program.Stimulation by the patient will then continue until the battery of thestimulator is depleted, or the patient decides to terminate thestimulation session. At that point, the patient will acknowledge thatthe stimulation session is finished by touching a response button on thesmartphone screen, whereupon the stimulator will transfer to the basestation data that its microprocessor has caused to be stored regardingthe stimulation session (e.g., stimulation amplitude as a function oftime and information about movements of the device during the session,duration of the stimulation, the existence of interruptions, etc.). Suchinformation will then be transmitted to and displayed by the patientinterface computer program (in the mobile phone or laptop computer),which will subsequently ask the patient questions regarding theeffectiveness of the stimulation. Such questions may be in regards tothe post-stimulation severity of the headache, whether the severitydecreased gradually or abruptly during the course of the stimulation,and whether anything unusual or noteworthy occurred during thestimulation. All such post-stimulation data will also be delivered overthe internet by the patient interface computer program to thephysician's computer for review and possible adjustment of the algorithmthat is used to select stimulation parameters and regimens. It isunderstood that the physician will adjust the algorithm based not onlyon the experience of each individual patient, but on the experience ofall patients collectively so as to improve effectiveness of thestimulator's use, for example, by identifying characteristics of mostand least responsive patients.

Before logging off of the interface computer program, the patient mayalso review database records and summaries about all previous treatmentsessions, so as to make his or her own judgment about treatmentprogress. If the stimulation was part of a prophylactic treatmentregimen that was prescribed by the patient's physician, the patientinterface computer program will remind the patient about the schedulefor the upcoming self-treatment sessions and allow for a rescheduling ifnecessary.

For some patients, the stimulation may be performed for as little as 90seconds, but it may also be for up to 30 minutes or longer. Thetreatment is generally performed once or twice daily or several times aweek, for 12 weeks or longer before a decision is made as to whether tocontinue the treatment. For patients experiencing intermittent symptoms,the treatment may be performed only when the patient is symptomatic.However, it is understood that parameters of the stimulation protocolmay be varied in response to heterogeneity in the pathophysiology ofpatients. Different stimulation parameters may also be used as thecourse of the patient's condition changes.

In some embodiments of the invention, pairing of vagus nerve stimulationmay be with a additional sensory stimulation. The paired sensorystimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. This pairing may beconsidered especially when some such corresponding sensory circuit ofthe brain is thought to be partly responsible for triggering themigraine headache.

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6,2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2,2006):179-84]. Thus, by performing the imaging with different setsof stimulation parameters, a database may be constructed, such that theinverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Alternatively, the selection of parameter values may involve tuning asunderstood in control theory, as described below. It is understood thatparameters may also be varied randomly in order to simulate normalphysiological variability, thereby possibly inducing a beneficialresponse in the patient [Buchman T G. Nonlinear dynamics, complexsystems, and the pathobiology of critical illness. Curr Opin Crit Care10(5,2004):378-82].

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve and to avoid potentially dangeroussituations such as excessive heart rate. Thus, with these methods, theparameters of the vagus nerve stimulation may be changed automatically,depending on environmental signals or on physiological measurements thatare made, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

When stimulating the vagus nerve, motion variability may often beattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 10).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 11 is a control theory representation of the disclosed vagus nervestimulation methods. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound, all of which may be triggers of amigraine attack. If the “System” is defined to be only a particularphysiological component of the patient, the “Environment” may also beconsidered to include physiological systems of the patient that are notincluded in the “System”. Thus, if some physiological component caninfluence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The system also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may comprisethe control unit 330 in FIG. 1C. Feedback in the schema shown in FIG. 11is possible because physiological measurements of the System are madeusing sensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3,2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212]. Such features would include EEG bands (e.g., delta,theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. Respiratory phase may also be inferred frommovement of the sternocleidomastoid muscle that also causes movement ofthe vagus nerve stimulator during breathing, measured usingaccelerometers attached to the vagus nerve stimulator, as describedbelow. After digitizing such signals, the phase of respiration may bedetermined using software such as “puka”, which is part ofPhysioToolkit, a large published library of open source software anduser manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov PCh, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley H E.PhysioBank, PhysioToolkit, and PhysioNet: Components of a New ResearchResource for Complex Physiologic Signals. Circulation101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A,77 Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment ofthe present invention, the control unit 330 contains ananalog-to-digital converter to receive such analog respiratory signals,and software for the analysis of the digitized respiratory waveformresides within the control unit 330. That software extracts turningpoints within the respiratory waveform, such as end-expiration andend-inspiration, and forecasts future turning points, based upon thefrequency with which waveforms from previous breaths match a partialwaveform for the current breath. The control unit 330 then controls theimpulse generator 310, for example, to stimulate the selected nerve onlyduring a selected phase of respiration, such as all of inspiration oronly the first second of inspiration, or only the expected middle halfof inspiration. In other embodiments of the invention, the physiologicalor environmental signals are transmitted wirelessly to the controller,as shown in FIG. 7. Some such signals may be received by the basestation (e.g., ambient sound signals) and other may be received withinthe stimulator housing (e.g., motion signals).

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the electrodes, depending on the phase of thepatient's respiration. In patent application JP2008/081479A, entitledVagus nerve stimulation system, to YOSHIHOTO, a system is also describedfor keeping the heart rate within safe limits. When the heart rate istoo high, that system stimulates a patient's vagus nerve, and when theheart rate is too low, that system tries to achieve stabilization of theheart rate by stimulating the heart itself, rather than use differentparameters to stimulate the vagus nerve. In that disclosure, vagalstimulation uses an electrode, which is described as either a surfaceelectrode applied to the body surface or an electrode introduced to thevicinity of the vagus nerve via a hypodermic needle. That disclosure isunrelated to the headache problems that are addressed here, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the electrodes, so as to achieve and maintain the heartrate within safe or desired limits. In that case, the parameters of thestimulation are individually raised or lowered in increments (power,frequency, etc.), and the effect as an increased, unchanged, ordecreased heart rate is stored in the memory of the control unit 330.When the heart rate changes to a value outside the specified range, thecontrol unit 330 automatically resets the parameters to values that hadbeen recorded to produce a heart rate within that range, or if no heartrate within that range has yet been achieved, it increases or decreasesparameter values in the direction that previously acquired data indicatewould change the heart rate in the direction towards a heart rate in thedesired range. Similarly, the arterial blood pressure is also recordednon-invasively in an embodiment of the invention, and as describedabove, the control unit 330 extracts the systolic, diastolic, and meanarterial blood pressure from the blood pressure waveform. The controlunit 330 will then control the impulse generator 310 in such a way as totemporally modulate nerve stimulation by the electrodes, in such a wayas to achieve and maintain the blood pressure within predetermined safeor desired limits, by the same method that was indicated above for theheart rate.

Let the measured output variables of the system in FIG. 11 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). In some embodiments, an objectivefor a controller is to select the input u_(j) in such a way that theoutput variables (or a subset of them) closely follows the referencesignals r_(i), i.e., the control error e_(i)=r_(i)−y_(i) is small, evenif there is environmental input or noise to the system. Consider theerror function e_(i)=r_(i)−y_(i) to be the sensed physiological input tothe controller in FIG. 11 (i.e., the reference signals are integral tothe controller, which subtracts the measured system values from them toconstruct the control error signal). The controller will also receive aset of measured environmental signals v_(k) (k=1 to R), which also actupon the system as shown in FIG. 11.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2B and 2C. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. In one embodiment, one or more accelerometer isattached to the patient's neck, and one or more accelerometer isattached to the head(s) of the stimulator in the vicinity of where thestimulator contacts the patient, or an accelerometer within thesmartphone is used. Because the temporally integrated outputs of theaccelerometers provide a measurement of the current position of eachaccelerometer, the combined accelerometer outputs make it possible tomeasure any movement of the stimulator relative to the underlyingtissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1,1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed or helped to perform neckmovements, breathe deeply so as to contract the sternocleidomastoidmuscle, and generally simulate possible motion that may accompanyprolonged stimulation with the stimulator. This would include possibleslippage or movement of the stimulator relative to an initial positionon the patient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data. Such data would complement imaging datathat measure the extent to which the current fluorescence images of thespots on the patient's neck coincide with a reference image, andtherefore also measure the relative movement of the stimulator.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurto,Przemystaw Ptonecki, Jacek Starzynski, Stanislaw Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(i)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}\ d\;\tau}}} + {K_{d}\frac{de}{dt}}}$where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative). Commercial versions of PIDcontrollers are available, and they are used in 90% of all controlapplications.

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [L I, Y., Ang, K. H. and Chong, G. C. Y. Patents, softwareand hardware for PID control: an overview and analysis of the currentart. IEEE Control Systems Magazine, 26 (1,2006): 42-54; Karl JohanAstrom & Richard M. Murray. Feedback Systems: An Introduction forScientists and Engineers. Princeton N.J.:Princeton University Press,2008; Finn HAUGEN. Tuning of PID controllers (Chapter 10) In: BasicDynamics and Control. 2009. ISBN 978-82-91748-13-9. TechTeach,Enggravhøgda 45, N-3711 Skien, Norway. http://techteach.no., pp.129-155; Dingyu XUE, YangQuan Chen, Derek P. Atherton. PID controllerdesign (Chapter 6), In: Linear Feedback Control: Analysis and Designwith MATLAB. Society for Industrial and Applied Mathematics (SIAM).3600Market Street, 6th Floor, Philadelphia, Pa. (2007), pp. 183-235; JanJANTZEN, Tuning Of Fuzzy PID Controllers, Technical University ofDenmark, report 98-H 871, Sep. 30, 1998].

The controller shown in FIG. 11 may also make use of feed-forwardmethods [Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9)In: Techniques of Model-Based Control. Upper Saddle River, N.J.:Prentice Hall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 9may be a type of predictive controller, methods for which have beendeveloped in other contexts as well, such as when a model of the systemis used to calculate future outputs of the system, with an objective ofchoosing among possible inputs so as to optimize a criterion that isbased on future values of the system's output variables.

A disclosure of the use of such feedback and feed forward methods toforecast and avert the onset of an imminent migraine attack was made inthe co-pending, commonly assigned application U.S. Ser. No. 13/357,010(publication US 2012/0185020), entitled Nerve stimulation methods foraverting imminent onset or episode of a disease, to SIMON et al, whichis incorporated by reference.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A method for treating a patient with aneurodegenerative disease, the method comprising: receiving anelectrical signal at a mobile phone hosting a handheld stimulatorincluding a contact surface, wherein the mobile phone receives theelectrical signal from a signal source external to the mobile phone;contacting an outer surface of a skin of the patient with the contactsurface; applying, as the contact surface contacts the outer surface, anelectrical impulse, formed based on the electrical signal, from thecontact surface to the outer surface such that the electrical impulsepasses from the outer surface transcutaneously through the skin to avagus nerve within a body of the patient, wherein the electrical impulsemodulates the vagus nerve and thereby modifies the neurodegenerativedisease; and causing a function of the mobile phone to be disabled asthe electrical impulse is applied from the contact surface to the outersurface, wherein the function is other than stimulation control.
 2. Themethod of claim 1, wherein the electrical impulse increases aninhibitory neurotransmitter in a brain of the patient such that anactivity of a microglial cell of the patient is modified.
 3. The methodof claim 2, wherein the electrical impulse transitions the microglialcell from a M1 phenotype state to an M2 phenotype state, therebycounteracting a neuroinflammation in the brain of the patient.
 4. Themethod of claim 1, wherein the neurodegenerative disease comprises atleast one of a dementia or an Alzheimer's disease.
 5. The method ofclaim 1, wherein the neurodegenerative disease comprises apost-traumatic concussion.
 6. The method of claim 1, wherein theneurodegenerative disease comprises an ischemic stroke.
 7. The method ofclaim 1, further comprising: prophylactically treating theneurodegenerative disease with a treatment regimen, wherein thetreatment regimen comprises continuously applying the electrical impulsefor a time period from about 30 seconds to about 300 seconds as a singledose and wherein the treatment regimen comprises applying a single doseon a daily basis.
 8. The method of claim 7 wherein the treatment regimencomprises applying from 2 to 5 single doses per day.
 9. The method ofclaim 1, wherein the mobile phone includes a housing, wherein thehousing includes the contact surface.
 10. The method of claim 1, whereinthe mobile phone is encased in a case, wherein the case includes thecontact surface.
 11. The method of claim 1, wherein the wirelesslytransmitting the electric signal includes downloading a mobileapplication software onto the mobile phone.
 12. The method of claim 11further comprising amplifying the electric signal.
 13. The method ofclaim 12, wherein the amplifying is performed within the handheldstimulator.
 14. The method of claim 12, wherein the amplifying includeselectrically coupling an amplifier to at least one of the mobile phoneor the handheld stimulator.
 15. The method of claim 1, wherein the outersurface extends along a neck of the patient.
 16. The method of claim 1,wherein the electrical impulse comprises bursts of pulses with each ofthe bursts having a frequency from about 1 to about 100 bursts persecond and each of the pulses having a frequency from about 1 to about20 KHz.
 17. The method of claim 1, further comprising: wirelesslytransmitting data for an electrical stimulation therapy to the mobilephone.
 18. The method of claim 17, wherein the wirelessly transmittingdata includes downloading a mobile application software program onto themobile phone.
 19. The method of claim 1, wherein the contact surfaceincludes an electrode that is integrated into the mobile phone.
 20. Themethod of claim 1, wherein the contact surface includes an electrodethat is removably coupled to the mobile phone.
 21. The method of claim1, wherein the electrical signal includes an audio waveform, wherein theelectrical impulse is formed based on the audio waveform.
 22. The methodof claim 1, wherein the handheld stimulator includes an electrode, andfurther comprising: filtering a high frequency component of theelectrical impulse between the electrode and the contact surface. 23.The method of claim 22, wherein the handheld stimulator includes anelectrically conductive fluid positioned between the electrode and thecontact surface.
 24. The method of claim 22, wherein the handheldstimulator includes a low-pass filter positioned between the electrodeand the contact surface.
 25. A method for treating a patient with aneurodegenerative disease, the method comprising: receiving a signal ata mobile phone from a signal source external to the mobile phone,wherein the mobile phone includes a housing, an electrode, and a contactsurface, wherein the housing hosts the electrode and the contactsurface, wherein the electrode is spaced apart from the contact surface,wherein the electrode resides within the housing; positioning thecontact surface in contact with an outer surface of a skin of thepatient; and applying, as the contact surface is in contact with theouter surface, an electrical impulse, formed based on the signal, fromthe electrode through the contact surface to the outer surface such thatthe electrical impulse passes from the outer surface through the skin toa vagus nerve within the patient, wherein the electrical impulsemodulates the vagus nerve and thereby modifies the neurodegenerativedisease.
 26. A method for treating a patient with a neurodegenerativedisease, the method comprising: receiving a signal at a mobile phonefrom a signal source external to the mobile phone, wherein the mobilephone includes a housing, wherein the housing is encased in a case,wherein the case includes a contact surface; positioning the contactsurface in contact with an outer surface of a skin of the patient; andapplying, as the contact surface is in contact with the outer surface,an electrical impulse, formed based on the signal, from the contactsurface to the outer surface such that the electrical impulse passesfrom the outer surface through the skin to a vagus nerve within thepatient, wherein the electrical impulse modulates the vagus nerve andthereby modifies the neurodegenerative disease.